Jak inhibitors

ABSTRACT

Described herein are Janus kinase (JAK) inhibitors and methods of utilizing JAK inhibitors in the treatment of diseases, disorders or conditions. Also described herein are pharmaceutical compositions containing such compounds.

CROSS-REFERENCE

This application claims benefit of U.S. Provisional Application No.62/884,593, filed on Aug. 8, 2019, which is herein incorporated byreference in its entirety.

BACKGROUND OF THE INVENTION

Janus kinase (JAK) is a family of intracellular, nonreceptor tyrosinekinases that transduce cytokine-mediated signals via the JAK-STATpathway. The four JAK family members are Janus kinase 1 (JAK1), Januskinase 2 (JAK2), Janus kinase 3 (JAK3), and Tyrosine kinase 2 (TYK2) andhave been shown to be key components of cytokine-mediated effects. Thecritical function of JAKs in cytokine signaling has implicated JAKinhibitors as potential therapeutics for a variety of diseases,including autoimmune and inflammatory diseases.

SUMMARY OF THE INVENTION

In one aspect, provided herein are compounds of Formula (I′):

wherein:

is phenyl or a C₂-C₉heteroaryl ring;

is a C₂-C₉heterocycloalkyl ring;

X is C(R₁₁) or N;

L₁ is C₁-C₆alkyl or C₁-C₆heteroalkyl;

L₂ is a bond or C₁-C₆alkyl;

R₁ is C₃-C₉alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, orC₂-C₉heteroaryl, wherein C₃-C₉alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₆cycloalkyl, or C₂-C₉heteroaryl are optionally substituted with 1,2, or 3 R₅;

each R₃ is independently selected from halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆heteroalkyl, —OR₇, —N(R₇)₂, —CN, —C(═O)R₈,—C(═O)OR₇, —C(═O)N(R₇)₂, —NR₇C(═O)R₈, —NR₇S(═O)₂R₈, —S(═O)₂R₈, and—S(═O)₂N(R₇)₂;

R₄ is hydrogen, C₁-C₆alkyl, or C₁-C₆heteroalkyl;

each R₅ is independently selected from halogen, oxo, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆heteroalkyl, —OR₇, —N(R₇)₂, —CN, —C(═O)R₈,—C(═O)OR₇, —C(═O)N(R₇)₂, —NR₇C(═O)R₈, —NR₇S(═O)₂R₈, —S(═O)₂R₈, and—S(═O)₂N(R₇)₂;

each R₇ is independently selected from hydrogen, C₁-C₆alkyl,C₂-C₆alkenyl, C₁-C₆haloalkyl, and C₁-C₆heteroalkyl;

each R₈ is independently selected from C₁-C₆alkyl, C₂-C₆alkenyl,C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;

R₁₁ is hydrogen or C₁-C₆alkyl optionally substituted with 1, 2, or 3 R₅;

R₁₂ is hydrogen, halogen, or C₁-C₆alkyl;

R₁₃ is selected from hydrogen and C₁-C₆alkyl;

each R₁₄ is independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆heteroalkyl, —OR₇, —N(R₇)₂, and oxo;

n is 0, 1, 2, or 3; and

p is 0, 1, 2, or 3;

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments is a compound of Formula (I′), or a pharmaceuticallyacceptable salt or solvate thereof, wherein

is a C₂-C₉heteroaryl ring. In some embodiments is a compound of Formula(I′), or a pharmaceutically acceptable salt or solvate thereof, wherein

is selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl,pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, and triazinyl. In some embodiments is a compound of Formula(I′), or a pharmaceutically acceptable salt or solvate thereof, wherein

is selected from pyrazolyl, pyrrolyl, and imidazolyl.

In some embodiments is a compound of Formula (I′), or a pharmaceuticallyacceptable salt or solvate thereof, having the structure of Formula(Ia′):

In some embodiments is a compound of Formula (I′) or (Ia′), or apharmaceutically acceptable salt or solvate thereof, wherein

is a pyrrolidine ring. In some embodiments is a compound of Formula (I′)or (Ia′), or a pharmaceutically acceptable salt or solvate thereof,wherein each R₁₄ is independently selected from C₁-C₆alkyl,C₁-C₆haloalkyl, and oxo. In some embodiments is a compound of Formula(I′) or (Ia′), or a pharmaceutically acceptable salt or solvate thereof,wherein each R₁₄ is independently selected from C₁-C₆alkyl. In someembodiments is a compound of Formula (I′) or (Ia′), or apharmaceutically acceptable salt or solvate thereof, wherein p is 1. Insome embodiments is a compound of Formula (I′) or (Ia′), or apharmaceutically acceptable salt or solvate thereof, wherein p is 0.

In another aspect, provided herein are compounds of Formula (I):

wherein:

is phenyl or a C₂-C₉heteroaryl ring;

X is C(R₁₁) or N;

L₁ is C₁-C₆alkyl or C₁-C₆heteroalkyl;

L₂ is a bond or C₁-C₆alkyl;

R₁ is C₃-C₉alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, orC₂-C₉heteroaryl, wherein C₃-C₉alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₆cycloalkyl, or C₂-C₉heteroaryl are optionally substituted with 1,2, or 3 R₅;

R₂ is —C(═O)OR₆;

each R₃ is independently selected from halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆heteroalkyl, —OR₇, —N(R₇)₂, —CN, —C(═O)R₈,—C(═O)OR₇, —C(═O)N(R₇)₂, —NR₇C(═O)R₈, —NR₇S(═O)₂R₈, —S(═O)₂R₈, and—S(═O)₂N(R₇)₂;

R₄ is hydrogen, C₁-C₆alkyl, or C₁-C₆heteroalkyl;

each R₅ is independently selected from halogen, oxo, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆heteroalkyl, —OR₇, —N(R₇)₂, —CN, —C(═O)R₈,—C(═O)OR₇, —C(═O)N(R₇)₂, —NR₇C(═O)R₈, —NR₇S(═O)₂R₈, —S(═O)₂R₈, and—S(═O)₂N(R₇)₂;

R₆ is C₂-C₉heterocycloalkyl substituted with 2 groups selected fromC₁-C₆alkyl and —C(═O)OR₁₃;

each R₇ is independently selected from hydrogen, C₁-C₆alkyl,C₂-C₆alkenyl, C₁-C₆haloalkyl, and C₁-C₆heteroalkyl;

each R₈ is independently selected from C₁-C₆alkyl, C₂-C₆alkenyl,C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;

R₁₁ is hydrogen or C₁-C₆alkyl optionally substituted with 1, 2, or 3 R₅;

R₁₂ is hydrogen, halogen, or C₁-C₆alkyl;

each R₁₃ is independently selected from hydrogen and C₁-C₆alkyl; and

n is 0, 1, 2, or 3;

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein

is phenyl. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein

is a C₂-C₉heteroaryl ring. In some embodiments is a compound of Formula(I), or a pharmaceutically acceptable salt or solvate thereof, wherein

is selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl,pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, and triazinyl. In some embodiments is a compound of Formula(I), or a pharmaceutically acceptable salt or solvate thereof, wherein

is selected from pyrazolyl, pyrrolyl, and imidazolyl. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein

is selected from

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein

In some embodiments is a compound of Formula (I′), (Ia′), or (I), or apharmaceutically acceptable salt or solvate thereof, wherein L₂ isC₁-C₆alkyl. In some embodiments is a compound of Formula (I′), (Ia′), or(I), or a pharmaceutically acceptable salt or solvate thereof, whereinL₂ is a bond. In some embodiments is a compound of Formula (I′), (Ia′),or (I), or a pharmaceutically acceptable salt or solvate thereof,wherein L₁ is C₁-C₆alkyl. In some embodiments is a compound of Formula(I′), (Ia′), or (I), or a pharmaceutically acceptable salt or solvatethereof, wherein R₁ is C₃-C₉alkyl, C₃-C₆cycloalkyl, or C₂-C₉heteroaryl,wherein C₃-C₉alkyl, C₃-C₆cycloalkyl, or C₂-C₉heteroaryl are optionallysubstituted with 1, 2, or 3 R₅ and C₂-C₉heteroaryl is selected fromoxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl,triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, andthiadiazolyl. In some embodiments is a compound of Formula (I′), (Ia′),or (I), or a pharmaceutically acceptable salt or solvate thereof,wherein each R₅ is independently selected from halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, —OR₇, and —N(R₇)₂. In some embodiments is a compound ofFormula (I′), (Ia′), or (I), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₁ is unsubstituted C₃-C₉alkyl. In someembodiments is a compound of Formula (I′), (Ia′), or (I), or apharmaceutically acceptable salt or solvate thereof, wherein R₁ isunsubstituted C₃-C₆cycloalkyl. In some embodiments is a compound ofFormula (I′), (Ia′), or (I), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₁ is unsubstituted C₂-C₉heteroaryl selectedfrom oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl,imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, and thiadiazolyl.

In some embodiments is a compound of Formula (I′), (Ia′), or (I), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ ishydrogen. In some embodiments is a compound of Formula (I′), (Ia′), or(I), or a pharmaceutically acceptable salt or solvate thereof, whereinR₄ is C₁-C₆alkyl. In some embodiments is a compound of Formula (I′),(Ia′), or (I), or a pharmaceutically acceptable salt or solvate thereof,wherein R₁₂ is hydrogen. In some embodiments is a compound of Formula(I′), (Ia′), or (I), or a pharmaceutically acceptable salt or solvatethereof, wherein R₁₂ is halogen. In some embodiments is a compound ofFormula (I′), (Ia′), or (I), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₁₂ is C₁-C₆alkyl. In some embodiments is acompound of Formula (I′), (Ia′), or (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein n is 0. In some embodimentsis a compound of Formula (I′), (Ia′), or (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein n is 1. In some embodimentsis a compound of Formula (I′), (Ia′), or (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₃ is selected from halogen,C₁-C₆alkyl, C₁-C₆haloalkyl, —OR₇, and —N(R₇)₂. In some embodiments is acompound of Formula (I′), (Ia′), or (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein each R₇ is independentlyselected from hydrogen and C₁-C₆alkyl. In some embodiments is a compoundof Formula (I′), (Ia′), or (I), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₃ is C₁-C₆alkyl. In some embodiments is acompound of Formula (I′), (Ia′), or (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is C(R₁₁). In someembodiments is a compound of Formula (I′), (Ia′), or (I), or apharmaceutically acceptable salt or solvate thereof, wherein X is C(H).In some embodiments is a compound of Formula (I′), (Ia′), or (I), or apharmaceutically acceptable salt or solvate thereof, wherein X is N.

In another aspect, provided herein are compounds of Formula (Ia):

wherein:

L₁ is a bond or C₁-C₆alkyl;

L₂ is C₁-C₆alkyl;

R₁ is C₁-C₉alkyl, C₃-C₆cycloalkyl, or C₂-C₉heteroaryl, whereinC₁-C₉alkyl, C₃-C₆cycloalkyl, or C₂-C₉heteroaryl are optionallysubstituted with 1, 2, or 3 R₅;

R₂ is —C(═O)OR₆;

each R₅ is independently selected from halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆heteroalkyl, —OR₇, —N(R₇)₂, —CN, —C(═O)R₈,—C(═O)OR₇, —C(═O)N(R₇)₂, —NR₇C(═O)R₈, —NR₇S(═O)₂R₈, —S(═O)₂R₈, and—S(═O)₂N(R₇)₂;

R₆ is C₂-C₉heterocycloalkyl substituted with 2 groups selected fromC₁-C₆alkyl and —C(═O)OR₁₃;

each R₇ is independently selected from hydrogen, C₁-C₆alkyl,C₂-C₆alkenyl, C₁-C₆haloalkyl, and C₁-C₆heteroalkyl;

each R₈ is independently selected from C₁-C₆alkyl, C₂-C₆alkenyl,C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl; and

each R₁₃ is independently selected from hydrogen and C₁-C₆alkyl;

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt or solvate thereof, wherein L₁ is C₁-C₆alkyl. In someembodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁ is C₁-C₉alkyl,C₃-C₆cycloalkyl, or C₂-C₉heteroaryl, wherein C₁-C₉alkyl,C₃-C₆cycloalkyl, or C₂-C₉heteroaryl are optionally substituted with 1,2, or 3 R₅ and C₂-C₉heteroaryl is selected from oxazolyl, thiazolyl,pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl,tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl. Insome embodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt or solvate thereof, wherein each R₅ is independentlyselected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, —OR₇, and —N(R₇)₂. Insome embodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁ is unsubstitutedC₁-C₉alkyl. In some embodiments is a compound of Formula (Ia), or apharmaceutically acceptable salt or solvate thereof, wherein R₁ isunsubstituted C₃-C₆cycloalkyl. In some embodiments is a compound ofFormula (Ia), or a pharmaceutically acceptable salt or solvate thereof,wherein R₁ is unsubstituted C₂-C₉heteroaryl selected from oxazolyl,thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl,tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl.

In some embodiments is a compound of Formula (I) or (Ia), or apharmaceutically acceptable salt or solvate thereof, wherein R₆ isC₂-C₉heterocycloalkyl substituted with 2 groups selected from C₁-C₆alkyland —C(═O)OR₁₃, wherein one group is C₁-C₆alkyl and one group is—C(═O)OR₁₃. In some embodiments is a compound of Formula (I) or (Ia), ora pharmaceutically acceptable salt or solvate thereof, wherein R₆ ispyrrolidinyl substituted with 2 groups selected from C₁-C₆alkyl and—C(═O)OR₁₃, wherein one group is C₁-C₆alkyl and one group is —C(═O)OR₁₃.

In some embodiments is a compound of Formula (I′), (Ia′), (I), or (Ia),or a pharmaceutically acceptable salt or solvate thereof, wherein R₁₃ isC₁-C₆alkyl. In some embodiments is a compound of Formula (I′), (Ia′),(I), or (Ia), or a pharmaceutically acceptable salt or solvate thereof,wherein R₁₃ is hydrogen.

In another aspect described herein is a pharmaceutical compositioncomprising a compound of Formula (I′), (Ia′), (I), or (Ia), or apharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable excipient.

In another aspect described herein is a method of treating aninflammatory or autoimmune disease in a patient in need thereof,comprising administering to the patient a therapeutically effectiveamount of a compound of Formula (I′), (Ia′), (I), or (Ia), or apharmaceutically acceptable salt or solvate thereof. In some embodimentsis a method of treating an inflammatory or autoimmune disease in apatient in need thereof, comprising administering to the individual atherapeutically effective amount of a compound of Formula (I′), (Ia′),(I), or (Ia), or a pharmaceutically acceptable salt or solvate thereof,wherein the disease is selected from rheumatoid arthritis, multiplesclerosis, psoriasis, lupus, intestinal bowel disease, Crohn's disease,ulcerative colitis, ankylosing spondylitis, vitiligo, and atopicdermatitis.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION Definitions

In the context of this disclosure, a number of terms shall be utilized.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood to which the claimedsubject matter belongs. In the event that there are a plurality ofdefinitions for terms herein, those in this section prevail. Allpatents, patent applications, publications and published nucleotide andamino acid sequences (e.g., sequences available in GenBank or otherdatabases) referred to herein are incorporated by reference. Wherereference is made to a URL or other such identifier or address, it isunderstood that such identifiers can change and particular informationon the internet can come and go, but equivalent information can be foundby searching the internet. Reference thereto evidences the availabilityand public dissemination of such information.

It is to be understood that the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of any subject matter claimed. In this application,the use of the singular includes the plural unless specifically statedotherwise. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. In thisapplication, the use of “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“include”, “includes,” and “included,” is not limiting.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.

Definition of standard chemistry terms may be found in reference works,including but not limited to, Carey and Sundberg “Advanced OrganicChemistry 4^(th) Ed.” Vols. A (2000) and B (2001), Plenum Press, NewYork. Unless otherwise indicated, conventional methods of massspectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinantDNA techniques and pharmacology.

Unless specific definitions are provided, the nomenclature employed inconnection with, and the laboratory procedures and techniques of,analytical chemistry, synthetic organic chemistry, and medicinal andpharmaceutical chemistry described herein are those recognized in thefield. Standard techniques can be used for chemical syntheses, chemicalanalyses, pharmaceutical preparation, formulation, and delivery, andtreatment of patients. Standard techniques can be used for recombinantDNA, oligonucleotide synthesis, and tissue culture and transformation(e.g., electroporation, lipofection). Reactions and purificationtechniques can be performed e.g., using kits of manufacturer'sspecifications or as commonly accomplished in the art or as describedherein. The foregoing techniques and procedures can be generallyperformed of conventional methods and as described in various generaland more specific references that are cited and discussed throughout thepresent specification.

It is to be understood that the methods and compositions describedherein are not limited to the particular methodology, protocols, celllines, constructs, and reagents described herein and as such may vary.It is also to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto limit the scope of the methods, compounds, compositions describedherein.

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x). C₁-C_(x)refers to the number of carbon atoms that make up the moiety to which itdesignates (excluding optional substituents).

An “alkyl” group refers to a straight or branched hydrocarbon chainradical consisting solely of carbon and hydrogen atoms, containing nounsaturation. In some embodiments, the “alkyl” group may have 1 to 6carbon atoms (whenever it appears herein, a numerical range such as “1to 6” refers to each integer in the given range; e.g., “1 to 6 carbonatoms” means that the alkyl group may consist of 1 carbon atom, 2 carbonatoms, 3 carbon atoms, etc., up to and including 6 carbon atoms,although the present definition also covers the occurrence of the term“alkyl” where no numerical range is designated). The alkyl group of thecompounds described herein may be designated as “C₁-C₆alkyl” or similardesignations. By way of example only, “C₁-C₆alkyl” indicates that thereare one to six carbon atoms in the alkyl chain, i.e., the alkyl chain isselected from the group consisting of methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl,iso-pentyl, neo-pentyl, and hexyl. Alkyl groups can be substituted orunsubstituted. Depending on the structure, an alkyl group can be amonoradical or a diradical (i.e., an alkylene group).

An “alkoxy” refers to a “—O-alkyl” group, where alkyl is as definedherein.

The term “alkenyl” refers to a straight or branched hydrocarbon chainradical group consisting solely of carbon and hydrogen atoms, containingat least one carbon-carbon double bond. Non-limiting examples of analkenyl group include —CH═CH₂, —C(CH₃)═CH₂, —CH═CHCH₃, —CH═C(CH₃)₂ and—C(CH₃)═CHCH₃. In some embodiments, an alkenyl groups may have 2 to 6carbons. Alkenyl groups can be substituted or unsubstituted. Dependingon the structure, an alkenyl group can be a monoradical or a diradical(i.e., an alkenylene group).

The term “alkynyl” refers to a straight or branched hydrocarbon chainradical group consisting solely of carbon and hydrogen atoms, containingat least one carbon-carbon triple bond. Non-limiting examples of analkynyl group include —C≡CH, —C≡CCH₃, —C≡CCH₂CH₃ and —C≡CCH₂CH₂CH₃. Insome embodiments, an alkynyl group can have 2 to 6 carbons. Alkynylgroups can be substituted or unsubstituted. Depending on the structure,an alkynyl group can be a monoradical or a diradical (i.e., analkynylene group).

“Amino” refers to a —NH₂ group.

The term “alkylamine” or “alkylamino” refers to the —N(alkyl)_(x)H_(y)group, where alkyl is as defined herein and x and y are selected fromthe group x=1, y=1 and x=2, y=0. When x=2, the alkyl groups, takentogether with the nitrogen to which they are attached, can optionallyform a cyclic ring system. “Dialkylamino” refers to a —N(alkyl)₂ group,where alkyl is as defined herein.

The term “aromatic” refers to a planar ring having a delocalizedπ-electron system containing 4n+2 π electrons, where n is an integer.Aromatic rings can be formed from five, six, seven, eight, nine, or morethan nine atoms. Aromatics can be optionally substituted. The term“aromatic” includes both aryl groups (e.g., phenyl, naphthalenyl) andheteroaryl groups (e.g., pyridinyl, quinolinyl).

As used herein, the term “aryl” refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. Aryl rings can be formedby five, six, seven, eight, nine, or more than nine carbon atoms. Arylgroups can be optionally substituted. Examples of aryl groups include,but are not limited to phenyl, and naphthalenyl. Depending on thestructure, an aryl group can be a monoradical or a diradical (i.e., anarylene group).

“Carboxy” refers to —CO₂H. In some embodiments, carboxy moieties may bereplaced with a “carboxylic acid bioisostere”, which refers to afunctional group or moiety that exhibits similar physical and/orchemical properties as a carboxylic acid moiety. A carboxylic acidbioisostere has similar biological properties to that of a carboxylicacid group. A compound with a carboxylic acid moiety can have thecarboxylic acid moiety exchanged with a carboxylic acid bioisostere andhave similar physical and/or biological properties when compared to thecarboxylic acid-containing compound. For example, in one embodiment, acarboxylic acid bioisostere would ionize at physiological pH to roughlythe same extent as a carboxylic acid group. Examples of bioisosteres ofa carboxylic acid include, but are not limited to,

and the like.

The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromaticradical, wherein each of the atoms forming the ring (i.e. skeletalatoms) is a carbon atom. Cycloalkyls may be saturated, or partiallyunsaturated. Cycloalkyls may be fused with an aromatic ring (in whichcase the cycloalkyl is bonded through a non-aromatic ring carbon atom).In some embodiments, cycloalkyl groups include groups having from 3 to10 ring atoms.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. An N-containing “heteroaromatic” or“heteroaryl” moiety refers to an aromatic group in which at least one ofthe skeletal atoms of the ring is a nitrogen atom.

A “heterocycloalkyl” group or “heteroalicyclic” group refers to acycloalkyl group, wherein at least one skeletal ring atom is aheteroatom selected from nitrogen, oxygen and sulfur. The radicals maybe fused with an aryl or heteroaryl. The term heteroalicyclic alsoincludes all ring forms of the carbohydrates, including but not limitedto the monosaccharides, the disaccharides and the oligosaccharides.Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons inthe ring. It is understood that when referring to the number of carbonatoms in a heterocycloalkyl, the number of carbon atoms in theheterocycloalkyl is not the same as the total number of atoms (includingthe heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atomsof the heterocycloalkyl ring).

The term “halo” or, alternatively, “halogen” means fluoro, chloro, bromoand iodo.

The term “haloalkyl” refers to an alkyl group that is substituted withone or more halogens. The halogens may the same or they may bedifferent. Non-limiting examples of haloalkyls include —CH₂Cl, —CF₃,—CHF₂, —CH₂CF₃, —CF₂CF₃, and the like.

The terms “fluoroalkyl” and “fluoroalkoxy” include alkyl and alkoxygroups, respectively, that are substituted with one or more fluorineatoms. Non-limiting examples of fluoroalkyls include —CF₃, —CHF₂, —CH₂F,—CH₂CF₃, —CF₂CF₃, —CF₂CF₂CF₃, —CF(CH₃)₃, and the like. Non-limitingexamples of fluoroalkoxy groups, include —OCF₃, —OCHF₂, —OCH₂F,—OCH₂CF₃, —OCF₂CF₃, —OCF₂CF₂CF₃, —OCF(CH₃)₂, and the like.

The term “heteroalkyl” refers to an alkyl radical where one or moreskeletal chain atoms is selected from an atom other than carbon, e.g.,oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof.The heteroatom(s) may be placed at any interior position of theheteroalkyl group. Examples include, but are not limited to, —CH₂—O—CH₃,—CH₂—CH₂—O—CH₃, —CH₂—NH—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—N(CH₃)—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂—S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —CH₂—NH—OCH₃, —CH₂—O—Si(CH₃)₃, —CH₂—CH═N—OCH₃, and—CH═CH—N(CH₃)—CH₃. In addition, up to two heteroatoms may beconsecutive, such as, by way of example, —CH₂—NH—OCH₃ and—CH₂—O—Si(CH₃)₃. Excluding the number of heteroatoms, a “heteroalkyl”may have from 1 to 6 carbon atoms.

“Oxo” refers to the ═O radical.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

As used herein, the substituent “R” appearing by itself and without anumber designation refers to a substituent selected from among fromalkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl(bonded through a ring carbon), and heterocycloalkyl.

“Optional” or “optionally” means that a subsequently described event orcircumstance may or may not occur and that the description includesinstances when the event or circumstance occurs and instances in whichit does not.

The term “optionally substituted” or “substituted” means that thereferenced group may be substituted with one or more additional group(s)individually and independently selected from alkyl, cycloalkyl, aryl,heteroaryl, heterocycloalkyl, —OH, alkoxy, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, —CN, alkyne,C₁-C₆alkylalkyne, halo, acyl, acyloxy, —CO₂H, —CO₂-alkyl, nitro,haloalkyl, fluoroalkyl, and amino, including mono- and di-substitutedamino groups (e.g. —NH₂, —NHR, —N(R)₂), and the protected derivativesthereof. By way of example, an optional substituents may be L^(s)R^(s),wherein each L is independently selected from a bond, —O—, —C(═O)—, —S—,—S(═O)—, —S(═O)₂—, —NH—, —NHC(O)—, —C(O)NH—, S(═O)₂NH—, —NHS(═O)₂,—OC(O)NH—, —NHC(O)O—, —(C₁-C₆alkyl)-, or —(C₂-C₆alkenyl)-; and eachR^(s) is independently selected from among H, (C₁-C₆alkyl),(C₃-C₈cycloalkyl), aryl, heteroaryl, heterocycloalkyl, andC₁-C₆heteroalkyl. The protecting groups that may form the protectivederivatives of the above substituents are found in sources such asGreene and Wuts, above.

As used herein, the term “about” or “approximately” means within 20%,preferably within 10%, and more preferably within 5% of a given value orrange.

The term a “therapeutically effective amount” as used herein refers tothe amount of a JAK inhibitor that, when administered to a mammal inneed, is effective to at least partially ameliorate or to at leastpartially prevent conditions related to skin aging.

As used herein, the term “expression” includes the process by whichpolynucleotides are transcribed into mRNA and translated into peptides,polypeptides, or proteins.

The term “modulate” encompasses either a decrease or an increase inactivity or expression depending on the target molecule.

The term “activator” is used in this specification to denote anymolecular species that results in activation of the indicated receptor,regardless of whether the species itself binds to the receptor or ametabolite of the species binds to the receptor when the species isadministered topically. Thus, the activator can be a ligand of thereceptor or it can be an activator that is metabolized to the ligand ofthe receptor, i.e., a metabolite that is formed in tissue and is theactual ligand.

The term “patient” or “mammal” refers to a human, a non-human primate,canine, feline, bovine, ovine, porcine, murine, or other veterinary orlaboratory mammal. Those skilled in the art recognize that a therapywhich reduces the severity of a pathology in one species of mammal ispredictive of the effect of the therapy on another species of mammal.

The term “soft-drug” as used herein, refers to drug substance and/or achemical compound that is biologically active in the desired targettissue and that is metabolized, after exerting its effect in the targettissue, to a compound that is inactive against the biological target. Insome embodiments, the soft-drug has no target biological activity insystemic circulation.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable salt of any one of the compoundsdescribed herein is intended to encompass any and all pharmaceuticallysuitable salt forms. Preferred pharmaceutically acceptable salts of thecompounds described herein are pharmaceutically acceptable acid additionsalts, and pharmaceutically acceptable base addition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,hydrofluoric acid, phosphorous acid, and the like. Also included aresalts that are formed with organic acids such as aliphatic mono- anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicacids, alkanedioic acids, aromatic acids, aliphatic and aromaticsulfonic acids, etc. and include, for example, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Exemplary salts thus include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates,malonates, succinate suberates, sebacates, fumarates, maleates,mandelates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,phenylacetates, citrates, lactates, malates, tartrates,methanesulfonates, and the like. Also contemplated are salts of aminoacids, such as arginates, gluconates, and galacturonates (see, forexample, Berge S. M. et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basiccompounds are prepared by contacting the free base forms with asufficient amount of the desired acid to produce the salt.

“Pharmaceutically acceptable base addition salt” refers to those saltsthat retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. In some embodiments, pharmaceutically acceptable baseaddition salts are formed with metals or amines, such as alkali andalkaline earth metals or organic amines. Salts derived from inorganicbases include, but are not limited to, sodium, potassium, lithium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminumsalts, and the like. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, for example,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine,hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline,N-methylglucamine, glucosamine, methylglucamine, theobromine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins, and thelike. See Berge et al., supra.

As used herein, “treatment” or “treating” or “palliating” or“ameliorating” are used interchangeably herein. These terms refer to anapproach for obtaining beneficial or desired results including but notlimited to therapeutic benefit and/or a prophylactic benefit. By“therapeutic benefit” is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient is still afflicted with the underlying disorder. Forprophylactic benefit, the compositions are administered to a patient atrisk of developing a particular disease, or to a patient reporting oneor more of the physiological symptoms of a disease, even though adiagnosis of this disease has not been made.

JAK Inhibitors

Cytokines are critical for host defense and immunoregulation, but arealso major players in the immunopathogenesis of autoimmune diseases.Based on structure, several major families of cytokines can berecognized. Two major classes are the so-called Type I and Type IIcytokine receptors. Type I receptors bind several interleukins (ILs),colony stimulating factors, and hormones such erythropoietin, prolactin,and growth hormone. Type II receptors bind interferons and IL-10 relatedcytokines. In contrast to other receptors, whose intracellular domainsencode kinase or other enzymatically active domains, these receptorslack such elements. Instead, the cytoplasmic domain of Type I and IIcytokine receptors bind to members of a specific kinase family, known asthe Janus kinases (JAKs) which include JAK1, JAK2, JAK3, and TYK2.Cytokine receptors are paired with different JAKs, which are activatedupon cytokine binding. Because JAKs are phosphotranferases, theycatalyze the transfer of phosphate from ATP to various substrates suchas cytokine receptors. This modification allows the recruitment ofvarious signaling molecules including members of the signal transducerand activator of transcription (STAT) family of DNA binding proteins.STATs are another important JAK substrate. Phosphorylation of STATspromotes their nuclear accumulation and regulation of gene expression.In addition, studies with knockout mice support the critical andspecific role of JAKs signaling by Type I/II cytokines and not otherpathways. The critical function of JAKs in cytokine signaling suggeststhe therapeutic potential of JAK inhibitors.

The compounds of Formula (I′), (Ia′), (I), or (Ia) described herein areJAK inhibitors. The compounds of Formula (I′), (Ia′), (I), or (Ia)described herein, and compositions comprising these compounds, areuseful for the treatment of an inflammatory or autoimmune disease.

In some embodiments, provided herein is a compound of Formula (I′), or apharmaceutically acceptable salt or solvate thereof:

wherein:

is phenyl or a C₂-C₉heteroaryl ring;

is a C₂-C₉heterocycloalkyl ring;

X is C(R₁₁) or N;

L₁ is C₁-C₆alkyl or C₁-C₆heteroalkyl;

L₂ is a bond or C₁-C₆alkyl;

R₁ is C₃-C₉alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, orC₂-C₉heteroaryl, wherein C₃-C₉alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₆cycloalkyl, or C₂-C₉heteroaryl are optionally substituted with 1,2, or 3 R₅;

each R₃ is independently selected from halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆heteroalkyl, —OR₇, —N(R₇)₂, —CN, —C(═O)R₈,—C(═O)OR₇, —C(═O)N(R₇)₂, —NR₇C(═O)R₈, —NR₇S(═O)₂R₈, —S(═O)₂R₈, and—S(═O)₂N(R₇)₂;

R₄ is hydrogen, C₁-C₆alkyl, or C₁-C₆heteroalkyl;

each R₅ is independently selected from halogen, oxo, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆heteroalkyl, —OR₇, —N(R₇)₂, —CN, —C(═O)R₈,—C(═O)OR₇, —C(═O)N(R₇)₂, —NR₇C(═O)R₈, —NR₇S(═O)₂R₈, —S(═O)₂R₈, and—S(═O)₂N(R₇)₂;

each R₇ is independently selected from hydrogen, C₁-C₆alkyl,C₂-C₆alkenyl, C₁-C₆haloalkyl, and C₁-C₆heteroalkyl;

each R₈ is independently selected from C₁-C₆alkyl, C₂-C₆alkenyl,C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;

R₁₁ is hydrogen or C₁-C₆alkyl optionally substituted with 1, 2, or 3 R₅;

R₁₂ is hydrogen, halogen, or C₁-C₆alkyl;

R₁₃ is selected from hydrogen and C₁-C₆alkyl;

each R₁₄ is independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆heteroalkyl, —OR₇, —N(R₇)₂, and oxo;

n is 0, 1, 2, or 3; and

p is 0, 1, 2, or 3;

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments is a compound of Formula (I′), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is C(R₁₁). In someembodiments is a compound of Formula (I′), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is C(H). In someembodiments is a compound of Formula (I′), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is N.

In some embodiments is a compound of Formula (I′), or a pharmaceuticallyacceptable salt or solvate thereof, wherein

is phenyl.

In some embodiments is a compound of Formula (I′), or a pharmaceuticallyacceptable salt or solvate thereof, wherein

is a C₂-C₉heteroaryl ring. In some embodiments is a compound of Formula(I′), or a pharmaceutically acceptable salt or solvate thereof, wherein

is a C₂-C₉heteroaryl ring selected from oxazolyl, thiazolyl, pyrazolyl,furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodimentsis a compound of Formula (I′), or a pharmaceutically acceptable salt orsolvate thereof, wherein

is a C₂-C₉heteroaryl ring selected from pyrazolyl, pyrrolyl, andimidazolyl.

In some embodiments is a compound of Formula (I′), or a pharmaceuticallyacceptable salt or solvate thereof, wherein

is a C₂-C₉heterocycloalkyl ring selected from selected from piperidinyl,piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl,pyrrolidinyl, oxetanyl, azetidinyl, and aziridinyl. In some embodimentsis a compound of Formula (I′), or a pharmaceutically acceptable salt orsolvate thereof, wherein

is a C₂-C₉heterocycloalkyl ring selected from selected from piperidinyl,piperazinyl, morpholinyl, tetrahydrofuranyl, and pyrrolidinyl. In someembodiments is a compound of Formula (I′), or a pharmaceuticallyacceptable salt or solvate thereof, wherein

is a pyrrolidinyl ring. In some embodiments is a compound of Formula(I′), or a pharmaceutically acceptable salt or solvate thereof, wherein

is a piperidinyl ring. In some embodiments is a compound of Formula(I′), or a pharmaceutically acceptable salt or solvate thereof, wherein

is a piperazinyl ring. In some embodiments is a compound of Formula(I′), or a pharmaceutically acceptable salt or solvate thereof, wherein

is a morpholinyl ring.

In some embodiments is a compound of Formula (I′), or a pharmaceuticallyacceptable salt or solvate thereof, wherein each R₁₄ is independentlyselected from C₁-C₆alkyl, C₁-C₆haloalkyl, and oxo. In some embodimentsis a compound of Formula (I′), or a pharmaceutically acceptable salt orsolvate thereof, wherein each R₁₄ is independently selected fromC₁-C₆alkyl. In some embodiments is a compound of Formula (I′), or apharmaceutically acceptable salt or solvate thereof, wherein p is 1. Insome embodiments is a compound of Formula (I′), or a pharmaceuticallyacceptable salt or solvate thereof, wherein p is 2. In some embodimentsis a compound of Formula (I′), or a pharmaceutically acceptable salt orsolvate thereof, wherein p is 0.

In some embodiments, provided herein is a compound of Formula (I′), or apharmaceutically acceptable salt or solvate thereof, wherein L₁ isC₁-C₆alkyl. In some embodiments, provided herein is a compound ofFormula (I′), or a pharmaceutically acceptable salt or solvate thereof,wherein L₁ is —CH₂—. In some embodiments, provided herein is a compoundof Formula (I′), or a pharmaceutically acceptable salt or solvatethereof, wherein L₁ is —CH₂CH₂—. In some embodiments, provided herein isa compound of Formula (I′), or a pharmaceutically acceptable salt orsolvate thereof, wherein L₁ is C₁-C₆heteroalkyl.

In some embodiments, provided herein is a compound of Formula (I′), or apharmaceutically acceptable salt or solvate thereof, wherein R₁ isC₃-C₉alkyl optionally substituted with 1, 2, or 3 R₅. In someembodiments, provided herein is a compound of Formula (I′), or apharmaceutically acceptable salt or solvate thereof, wherein R₁ isunsubstituted C₃-C₉alkyl. In some embodiments, provided herein is acompound of Formula (I′), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₁ is C₃-C₆cycloalkyl optionally substitutedwith 1, 2, or 3 R₅. In some embodiments, provided herein is a compoundof Formula (I′), or a pharmaceutically acceptable salt or solvatethereof, wherein R₁ is C₃-C₆cycloalkyl optionally substituted with 1, 2,or 3 R₅, wherein each R₅ is independently selected from halogen,C₁-C₆alkyl, C₁-C₆haloalkyl, —OR₇, and —N(R₇)₂. In some embodiments,provided herein is a compound of Formula (I′), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁ is C₃-C₆cycloalkyloptionally substituted with 1, 2, or 3 R₅, wherein each R₅ isindependently selected from halogen and C₁-C₆alkyl. In some embodiments,provided herein is a compound of Formula (I′), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁ is unsubstitutedC₃-C₆cycloalkyl. In some embodiments, provided herein is a compound ofFormula (I′), or a pharmaceutically acceptable salt or solvate thereof,wherein R₁ is C₂-C₉heteroaryl optionally substituted with 1, 2, or 3 R₅.In some embodiments, provided herein is a compound of Formula (I′), or apharmaceutically acceptable salt or solvate thereof, wherein R₁ isC₂-C₉heteroaryl optionally substituted with 1, 2, or 3 R₅, wherein eachR₅ is independently selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl,—OR₇, and —N(R₇)₂. In some embodiments, provided herein is a compound ofFormula (I′), or a pharmaceutically acceptable salt or solvate thereof,wherein R₁ is C₂-C₉heteroaryl optionally substituted with 1, 2, or 3 R₅,wherein each R₅ is independently selected from halogen and C₁-C₆alkyl.In some embodiments, provided herein is a compound of Formula (I′), or apharmaceutically acceptable salt or solvate thereof, wherein R₁ isunsubstituted C₂-C₉heteroaryl. In some embodiments, provided herein is acompound of Formula (I′), or a pharmaceutically acceptable salt orsolvate thereof, wherein C₂-C₉heteroaryl is selected from oxazolyl,thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl,tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl.

In some embodiments, provided herein is a compound of Formula (I′), or apharmaceutically acceptable salt or solvate thereof, wherein L₂ is abond. In some embodiments, provided herein is a compound of Formula(I′), or a pharmaceutically acceptable salt or solvate thereof, whereinL₂ is C₁-C₆alkyl. In some embodiments, provided herein is a compound ofFormula (I′), or a pharmaceutically acceptable salt or solvate thereof,wherein L₂ is —CH₂—. In some embodiments, provided herein is a compoundof Formula (I′), or a pharmaceutically acceptable salt or solvatethereof, wherein L₂ is —CH₂CH₂—. In some embodiments, provided herein isa compound of Formula (I′), or a pharmaceutically acceptable salt orsolvate thereof, wherein L₂ is —CH₂CH₂CH₂—.

In some embodiments, provided herein is a compound of Formula (I′), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₃ isC₁-C₆alkyl. In some embodiments, provided herein is a compound ofFormula (I′), or a pharmaceutically acceptable salt or solvate thereof,wherein R₁₃ is —CH₃. In some embodiments, provided herein is a compoundof Formula (I), or a pharmaceutically acceptable salt or solvatethereof, wherein R₁₃ is —CH₂CH₃. In some embodiments, provided herein isa compound of Formula (I′), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₁₃ is —C(H)(CH₃)₂. In some embodiments,provided herein is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁₃ is hydrogen.

In some embodiments, provided herein is a compound of Formula (I′), or apharmaceutically acceptable salt or solvate thereof, wherein n is 0.

In some embodiments, provided herein is a compound of Formula (I′), or apharmaceutically acceptable salt or solvate thereof, wherein n is 1. Insome embodiments, provided herein is a compound of Formula (I′), or apharmaceutically acceptable salt or solvate thereof, wherein n is 2. Insome embodiments, provided herein is a compound of Formula (I′), or apharmaceutically acceptable salt or solvate thereof, wherein n is 3. Insome embodiments, provided herein is a compound of Formula (I′), or apharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2and each R₃ is independently selected from halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆heteroalkyl, —OR₇, —N(R₇)₂, —CN, —C(═O)R₈,—C(═O)OR₇, —C(═O)N(R₇)₂, —NR₇C(═O)R₈, —NR₇S(═O)₂R₈, —S(═O)₂R₈, and—S(═O)₂N(R₇)₂. In some embodiments, provided herein is a compound ofFormula (I′), or a pharmaceutically acceptable salt or solvate thereof,wherein n is 1 or 2 and each R₃ is independently selected from halogen,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆heteroalkyl, —OR₇, —N(R₇)₂, —CN,—C(═O)R₈, —C(═O)OR₇, —C(═O)N(R₇)₂, —NR₇C(═O)R₈, —NR₇S(═O)₂R₈, —S(═O)₂R₈,and —S(═O)₂N(R₇)₂. In some embodiments, provided herein is a compound ofFormula (I′), or a pharmaceutically acceptable salt or solvate thereof,wherein n is 1 or 2 and each R₃ is independently selected from halogen,C₁-C₆alkyl, C₁-C₆haloalkyl, —OR₇, and —N(R₇)₂. In some embodiments,provided herein is a compound of Formula (I′), or a pharmaceuticallyacceptable salt or solvate thereof, wherein n is 1 or 2 and each R₃ isindependently selected from halogen and C₁-C₆alkyl. In some embodiments,provided herein is a compound of Formula (I′), or a pharmaceuticallyacceptable salt or solvate thereof, wherein n is 1 and R₃ is selectedfrom halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, —OR₇, and —N(R₇)₂. In someembodiments, provided herein is a compound of Formula (I′), or apharmaceutically acceptable salt or solvate thereof, wherein n is 1 andR₃ is selected from halogen and C₁-C₆alkyl. In some embodiments,provided herein is a compound of Formula (I′), or a pharmaceuticallyacceptable salt or solvate thereof, wherein n is 1 and R₃ is halogen. Insome embodiments, provided herein is a compound of Formula (I′), or apharmaceutically acceptable salt or solvate thereof, wherein n is 1 andR₃ is C₁-C₆alkyl.

In some embodiments, provided herein is a compound of Formula (I′), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ ishydrogen. In some embodiments, provided herein is a compound of Formula(I′), or a pharmaceutically acceptable salt or solvate thereof, whereinR₄ is C₁-C₆alkyl. In some embodiments, provided herein is a compound ofFormula (I′), or a pharmaceutically acceptable salt or solvate thereof,wherein R₄ is —CH₃. In some embodiments, provided herein is a compoundof Formula (I′), or a pharmaceutically acceptable salt or solvatethereof, wherein R₄ is C₁-C₆heteroalkyl.

In some embodiments is a compound of Formula (I′), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁₂ is hydrogen. In someembodiments is a compound of Formula (I′), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁₂ is halogen. In someembodiments is a compound of Formula (I′), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁₂ is C₁-C₆alkyl. In someembodiments, provided herein is a compound of Formula (I′), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₂ is—CH₃.

In some embodiments is a compound of Formula (I′), or a pharmaceuticallyacceptable salt or solvate thereof, having the structure of Formula(Ia′):

wherein:

is a C₂-C₉heterocycloalkyl ring;

X is C(R₁₁) or N;

L₁ is C₁-C₆alkyl or C₁-C₆heteroalkyl;

L₂ is a bond or C₁-C₆alkyl;

R₁ is C₃-C₉alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, orC₂-C₉heteroaryl, wherein C₃-C₉alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₆cycloalkyl, or C₂-C₉heteroaryl are optionally substituted with 1,2, or 3 R₅;

R₄ is hydrogen, C₁-C₆alkyl, or C₁-C₆heteroalkyl;

each R₅ is independently selected from halogen, oxo, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆heteroalkyl, —OR₇, —N(R₇)₂, —CN, —C(═O)R₈,—C(═O)OR₇, —C(═O)N(R₇)₂, —NR₇C(═O)R₈, —NR₇S(═O)₂R₈, —S(═O)₂R₈, and—S(═O)₂N(R₇)₂;

each R₇ is independently selected from hydrogen, C₁-C₆alkyl,C₂-C₆alkenyl, C₁-C₆haloalkyl, and C₁-C₆heteroalkyl;

each R₈ is independently selected from C₁-C₆alkyl, C₂-C₆alkenyl,C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;

R₁₁ is hydrogen or C₁-C₆alkyl optionally substituted with 1, 2, or 3 R₅;

R₁₂ is hydrogen, halogen, or C₁-C₆alkyl;

R₁₃ is selected from hydrogen and C₁-C₆alkyl;

each R₁₄ is independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆heteroalkyl, —OR₇, —N(R₇)₂, and oxo; and

p is 0, 1, 2, or 3;

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments is a compound of Formula (Ia′), or apharmaceutically acceptable salt or solvate thereof, wherein X isC(R₁₁). In some embodiments is a compound of Formula (Ia′), or apharmaceutically acceptable salt or solvate thereof, wherein X is C(H).In some embodiments is a compound of Formula (Ia′), or apharmaceutically acceptable salt or solvate thereof, wherein X is N.

In some embodiments is a compound of Formula (Ia′), or apharmaceutically acceptable salt or solvate thereof, wherein

is a C₂-C₉heterocycloalkyl ring selected from selected from piperidinyl,piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl,pyrrolidinyl, oxetanyl, azetidinyl, and aziridinyl. In some embodimentsis a compound of Formula (Ia′), or a pharmaceutically acceptable salt orsolvate thereof, wherein

is a C₂-C₉heterocycloalkyl ring selected from selected from piperidinyl,piperazinyl, morpholinyl, tetrahydrofuranyl, and pyrrolidinyl. In someembodiments is a compound of Formula (Ia′), or a pharmaceuticallyacceptable salt or solvate thereof, wherein

is a pyrrolidinyl ring. In some embodiments is a compound of Formula(Ia′), or a pharmaceutically acceptable salt or solvate thereof, wherein

is a piperidinyl ring. In some embodiments is a compound of Formula(Ia′), or a pharmaceutically acceptable salt or solvate thereof, wherein

is a piperazinyl ring. In some embodiments is a compound of Formula(Ia′), or a pharmaceutically acceptable salt or solvate thereof, wherein

is a morpholinyl ring.

In some embodiments is a compound of Formula (Ia′), or apharmaceutically acceptable salt or solvate thereof, wherein each R₁₄ isindependently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, and oxo. In someembodiments is a compound of Formula (Ia′), or a pharmaceuticallyacceptable salt or solvate thereof, wherein each R₁₄ is independentlyselected from C₁-C₆alkyl. In some embodiments is a compound of Formula(Ia′), or a pharmaceutically acceptable salt or solvate thereof, whereinp is 1. In some embodiments is a compound of Formula (Ia′), or apharmaceutically acceptable salt or solvate thereof, wherein p is 2. Insome embodiments is a compound of Formula (Ia′), or a pharmaceuticallyacceptable salt or solvate thereof, wherein p is 0.

In some embodiments, provided herein is a compound of Formula (Ia′), ora pharmaceutically acceptable salt or solvate thereof, wherein L₁ isC₁-C₆alkyl. In some embodiments, provided herein is a compound ofFormula (Ia′), or a pharmaceutically acceptable salt or solvate thereof,wherein L₁ is —CH₂—. In some embodiments, provided herein is a compoundof Formula (Ia′), or a pharmaceutically acceptable salt or solvatethereof, wherein L₁ is —CH₂CH₂—. In some embodiments, provided herein isa compound of Formula (Ia′), or a pharmaceutically acceptable salt orsolvate thereof, wherein L₁ is C₁-C₆heteroalkyl.

In some embodiments, provided herein is a compound of Formula (Ia′), ora pharmaceutically acceptable salt or solvate thereof, wherein R₁ isC₃-C₉alkyl optionally substituted with 1, 2, or 3 R₅. In someembodiments, provided herein is a compound of Formula (Ia′), or apharmaceutically acceptable salt or solvate thereof, wherein R₁ isunsubstituted C₃-C₉alkyl. In some embodiments, provided herein is acompound of Formula (Ia′), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₁ is C₃-C₆cycloalkyl optionally substitutedwith 1, 2, or 3 R₅. In some embodiments, provided herein is a compoundof Formula (Ia′), or a pharmaceutically acceptable salt or solvatethereof, wherein R₁ is C₃-C₆cycloalkyl optionally substituted with 1, 2,or 3 R₅, wherein each R₅ is independently selected from halogen,C₁-C₆alkyl, C₁-C₆haloalkyl, —OR₇, and —N(R₇)₂. In some embodiments,provided herein is a compound of Formula (Ia′), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁ is C₃-C₆cycloalkyloptionally substituted with 1, 2, or 3 R₅, wherein each R₅ isindependently selected from halogen and C₁-C₆alkyl. In some embodiments,provided herein is a compound of Formula (Ia′), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁ is unsubstitutedC₃-C₆cycloalkyl. In some embodiments, provided herein is a compound ofFormula (Ia′), or a pharmaceutically acceptable salt or solvate thereof,wherein R₁ is C₂-C₉heteroaryl optionally substituted with 1, 2, or 3 R₅.In some embodiments, provided herein is a compound of Formula (Ia′), ora pharmaceutically acceptable salt or solvate thereof, wherein R₁ isC₂-C₉heteroaryl optionally substituted with 1, 2, or 3 R₅, wherein eachR₅ is independently selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl,—OR₇, and —N(R₇)₂. In some embodiments, provided herein is a compound ofFormula (Ia′), or a pharmaceutically acceptable salt or solvate thereof,wherein R₁ is C₂-C₉heteroaryl optionally substituted with 1, 2, or 3 R₅,wherein each R₅ is independently selected from halogen and C₁-C₆alkyl.In some embodiments, provided herein is a compound of Formula (Ia′), ora pharmaceutically acceptable salt or solvate thereof, wherein R₁ isunsubstituted C₂-C₉heteroaryl. In some embodiments, provided herein is acompound of Formula (Ia′), or a pharmaceutically acceptable salt orsolvate thereof, wherein C₂-C₉heteroaryl is selected from oxazolyl,thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl,tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl.

In some embodiments, provided herein is a compound of Formula (Ia′), ora pharmaceutically acceptable salt or solvate thereof, wherein L₂ is abond. In some embodiments, provided herein is a compound of Formula(Ia′), or a pharmaceutically acceptable salt or solvate thereof, whereinL₂ is C₁-C₆alkyl. In some embodiments, provided herein is a compound ofFormula (Ia′), or a pharmaceutically acceptable salt or solvate thereof,wherein L₂ is —CH₂—. In some embodiments, provided herein is a compoundof Formula (Ia′), or a pharmaceutically acceptable salt or solvatethereof, wherein L₂ is —CH₂CH₂—. In some embodiments, provided herein isa compound of Formula (Ia′), or a pharmaceutically acceptable salt orsolvate thereof, wherein L₂ is —CH₂CH₂CH₂—.

In some embodiments, provided herein is a compound of Formula (Ia′), ora pharmaceutically acceptable salt or solvate thereof, wherein R₁₃ isC₁-C₆alkyl. In some embodiments, provided herein is a compound ofFormula (Ia′), or a pharmaceutically acceptable salt or solvate thereof,wherein R₁₃ is —CH₃. In some embodiments, provided herein is a compoundof Formula (Ia′), or a pharmaceutically acceptable salt or solvatethereof, wherein R₁₃ is —CH₂CH₃. In some embodiments, provided herein isa compound of Formula (Ia′), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₁₃ is —C(H)(CH₃)₂. In some embodiments,provided herein is a compound of Formula (Ia′), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁₃ is hydrogen.

In some embodiments, provided herein is a compound of Formula (Ia′), ora pharmaceutically acceptable salt or solvate thereof, wherein R₄ ishydrogen. In some embodiments, provided herein is a compound of Formula(Ia′), or a pharmaceutically acceptable salt or solvate thereof, whereinR₄ is C₁-C₆alkyl. In some embodiments, provided herein is a compound ofFormula (Ia′), or a pharmaceutically acceptable salt or solvate thereof,wherein R₄ is —CH₃. In some embodiments, provided herein is a compoundof Formula (Ia′), or a pharmaceutically acceptable salt or solvatethereof, wherein R₄ is C₁-C₆heteroalkyl.

In some embodiments is a compound of Formula (Ia′), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₂ ishydrogen. In some embodiments is a compound of Formula (Ia′), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₂ ishalogen. In some embodiments is a compound of Formula (Ia′), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₂ isC₁-C₆alkyl. In some embodiments, provided herein is a compound ofFormula (Ia′), or a pharmaceutically acceptable salt or solvate thereof,wherein R₁₂ is —CH₃.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof:

wherein:

is phenyl or a C₂-C₉heteroaryl ring;

X is C(R₁₁) or N;

L₁ is C₁-C₆alkyl or C₁-C₆heteroalkyl;

L₂ is a bond or C₁-C₆alkyl;

R₁ is C₃-C₉alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, orC₂-C₉heteroaryl, wherein C₃-C₉alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₆cycloalkyl, or C₂-C₉heteroaryl are optionally substituted with 1,2, or 3 R₅;

R₂ is —C(═O)OR₆;

each R₃ is independently selected from halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆heteroalkyl, —OR₇, —N(R₇)₂, —CN, —C(═O)R₈,—C(═O)OR₇, —C(═O)N(R₇)₂, —NR₇C(═O)R₈, —NR₇S(═O)₂R₈, —S(═O)₂R₈, and—S(═O)₂N(R₇)₂;

R₄ is hydrogen, C₁-C₆alkyl, or C₁-C₆heteroalkyl;

each R₅ is independently selected from halogen, oxo, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆heteroalkyl, —OR₇, —N(R₇)₂, —CN, —C(═O)R₈,—C(═O)OR₇, —C(═O)N(R₇)₂, —NR₇C(═O)R₈, —NR₇S(═O)₂R₈, —S(═O)₂R₈, and—S(═O)₂N(R₇)₂;

R₆ is C₂-C₉heterocycloalkyl substituted 2 groups selected fromC₁-C₆alkyl and —C(═O)OR₁₃;

each R₇ is independently selected from hydrogen, C₁-C₆alkyl,C₂-C₆alkenyl, C₁-C₆haloalkyl, and C₁-C₆heteroalkyl;

each R₈ is independently selected from C₁-C₆alkyl, C₂-C₆alkenyl,C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl;

R₁₁ is hydrogen or C₁-C₆alkyl optionally substituted with 1, 2, or 3 R₅;

R₁₂ is hydrogen, halogen, or C₁-C₆alkyl;

each R₁₃ is independently selected from hydrogen and C₁-C₆alkyl; and

n is 0, 1, 2, or 3.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is C(R₁₁). In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is C(H). In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is N.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein

is phenyl.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein

is a C₂-C₉heteroaryl ring. In some embodiments is a compound of Formula(I), or a pharmaceutically acceptable salt or solvate thereof, wherein

is a C₂-C₉heteroaryl ring selected from oxazolyl, thiazolyl, pyrazolyl,furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodimentsis a compound of Formula (I), or a pharmaceutically acceptable salt orsolvate thereof, wherein

is a C₂-C₉heteroaryl ring selected from pyrazolyl, pyrrolyl, andimidazolyl. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein

is a C₂-C₉heteroaryl ring selected from

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof,

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein L₁ isC₁-C₆alkyl. In some embodiments, provided herein is a compound ofFormula (I), or a pharmaceutically acceptable salt or solvate thereof,wherein L₁ is —CH₂—. In some embodiments, provided herein is a compoundof Formula (I), or a pharmaceutically acceptable salt or solvatethereof, wherein L₁ is —CH₂CH₂—. In some embodiments, provided herein isa compound of Formula (I), or a pharmaceutically acceptable salt orsolvate thereof, wherein L₁ is C₁-C₆heteroalkyl.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein R₁ isC₃-C₉alkyl optionally substituted with 1, 2, or 3 R₅. In someembodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein R₁ isunsubstituted C₃-C₉alkyl. In some embodiments, provided herein is acompound of Formula (I), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₁ is C₃-C₆cycloalkyl optionally substitutedwith 1, 2, or 3 R₅. In some embodiments, provided herein is a compoundof Formula (I), or a pharmaceutically acceptable salt or solvatethereof, wherein R₁ is C₃-C₆cycloalkyl optionally substituted with 1, 2,or 3 R₅, wherein each R₅ is independently selected from halogen,C₁-C₆alkyl, C₁-C₆haloalkyl, —OR₇, and —N(R₇)₂. In some embodiments,provided herein is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁ is C₃-C₆cycloalkyloptionally substituted with 1, 2, or 3 R₅, wherein each R₅ isindependently selected from halogen and C₁-C₆alkyl. In some embodiments,provided herein is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁ is unsubstitutedC₃-C₆cycloalkyl. In some embodiments, provided herein is a compound ofFormula (I), or a pharmaceutically acceptable salt or solvate thereof,wherein R₁ is C₂-C₉heteroaryl optionally substituted with 1, 2, or 3 R₅.In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein R₁ isC₂-C₉heteroaryl optionally substituted with 1, 2, or 3 R₅, wherein eachR₅ is independently selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl,—OR₇, and —N(R₇)₂. In some embodiments, provided herein is a compound ofFormula (I), or a pharmaceutically acceptable salt or solvate thereof,wherein R₁ is C₂-C₉heteroaryl optionally substituted with 1, 2, or 3 R₅,wherein each R₅ is independently selected from halogen and C₁-C₆alkyl.In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein R₁ isunsubstituted C₂-C₉heteroaryl. In some embodiments, provided herein is acompound of Formula (I), or a pharmaceutically acceptable salt orsolvate thereof, wherein C₂-C₉heteroaryl is selected from oxazolyl,thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl,tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein L₂ is abond. In some embodiments, provided herein is a compound of Formula (I),or a pharmaceutically acceptable salt or solvate thereof, wherein L₂ isC₁-C₆alkyl. In some embodiments, provided herein is a compound ofFormula (I), or a pharmaceutically acceptable salt or solvate thereof,wherein L₂ is —CH₂—. In some embodiments, provided herein is a compoundof Formula (I), or a pharmaceutically acceptable salt or solvatethereof, wherein L₂ is —CH₂CH₂—. In some embodiments, provided herein isa compound of Formula (I), or a pharmaceutically acceptable salt orsolvate thereof, wherein L₂ is —CH₂CH₂CH₂—.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein R₂ is—C(═O)OR₆ and R₆ is C₂-C₉heterocycloalkyl substituted 2 groups selectedfrom C₁-C₆alkyl and —C(═O)OR₁₃, wherein one group is C₁-C₆alkyl and onegroup is —C(═O)OR₁₃. In some embodiments is a compound of Formula (I),or a pharmaceutically acceptable salt or solvate thereof, wherein R₆ isselected from piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl,and pyrrolidinyl, wherein piperidinyl, piperazinyl, morpholinyl,tetrahydrofuranyl, and pyrrolidinyl are substituted with 2 groupsselected from C₁-C₆alkyl and —C(═O)OR₁₃, wherein one group is C₁-C₆alkyland one group is —C(═O)OR₁₃. In some embodiments is a compound ofFormula (I), or a pharmaceutically acceptable salt or solvate thereof,wherein R₆ is pyrrolidinyl substituted with 2 groups selected fromC₁-C₆alkyl and —C(═O)OR₁₃, wherein one group is C₁-C₆alkyl and one groupis —C(═O)OR₁₃. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein R₆ ispiperidinyl substituted with 2 groups selected from C₁-C₆alkyl and—C(═O)OR₁₃, wherein one group is C₁-C₆alkyl and one group is —C(═O)OR₁₃.In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₆ is morpholinylsubstituted with 2 groups selected from C₁-C₆alkyl and —C(═O)OR₁₃,wherein one group is C₁-C₆alkyl and one group is —C(═O)OR₁₃. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₆ is piperazinylsubstituted with 2 groups selected from C₁-C₆alkyl and —C(═O)OR₁₃,wherein one group is C₁-C₆alkyl and one group is —C(═O)OR₁₃. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₆ is tetrahydrofuranylsubstituted with 2 groups selected from C₁-C₆alkyl and —C(═O)OR₁₃,wherein one group is C₁-C₆alkyl and one group is —C(═O)OR₁₃.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₃ isC₁-C₆alkyl. In some embodiments, provided herein is a compound ofFormula (I), or a pharmaceutically acceptable salt or solvate thereof,wherein R₁₃ is —CH₃. In some embodiments, provided herein is a compoundof Formula (I), or a pharmaceutically acceptable salt or solvatethereof, wherein R₁₃ is —CH₂CH₃. In some embodiments, provided herein isa compound of Formula (I), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₁₃ is —C(H)(CH₃)₂. In some embodiments,provided herein is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁₃ is hydrogen.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein n is 0.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein n is 1. Insome embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein n is 2. Insome embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein n is 3. Insome embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2and each R₃ is independently selected from halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆heteroalkyl, —OR₇, —N(R₇)₂, —CN, —C(═O)R₈,—C(═O)OR₇, —C(═O)N(R₇)₂, —NR₇C(═O)R₈, —NR₇S(═O)₂R₈, —S(═O)₂R₈, and—S(═O)₂N(R₇)₂. In some embodiments, provided herein is a compound ofFormula (I), or a pharmaceutically acceptable salt or solvate thereof,wherein n is 1 or 2 and each R₃ is independently selected from halogen,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆heteroalkyl, —OR₇, —N(R₇)₂, —CN,—C(═O)R₈, —C(═O)OR₇, —C(═O)N(R₇)₂, —NR₇C(═O)R₈, —NR₇S(═O)₂R₈, —S(═O)₂R₈,and —S(═O)₂N(R₇)₂. In some embodiments, provided herein is a compound ofFormula (I), or a pharmaceutically acceptable salt or solvate thereof,wherein n is 1 or 2 and each R₃ is independently selected from halogen,C₁-C₆alkyl, C₁-C₆haloalkyl, —OR₇, and —N(R₇)₂. In some embodiments,provided herein is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein n is 1 or 2 and each R₃ isindependently selected from halogen and C₁-C₆alkyl. In some embodiments,provided herein is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein n is 1 and R₃ is selectedfrom halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, —OR₇, and —N(R₇)₂. In someembodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein n is 1 andR₃ is selected from halogen and C₁-C₆alkyl. In some embodiments,provided herein is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein n is 1 and R₃ is halogen. Insome embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein n is 1 andR₃ is C₁-C₆alkyl.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein R₄ ishydrogen. In some embodiments, provided herein is a compound of Formula(I), or a pharmaceutically acceptable salt or solvate thereof, whereinR₄ is C₁-C₆alkyl. In some embodiments, provided herein is a compound ofFormula (I), or a pharmaceutically acceptable salt or solvate thereof,wherein R₄ is —CH₃. In some embodiments, provided herein is a compoundof Formula (I), or a pharmaceutically acceptable salt or solvatethereof, wherein R₄ is C₁-C₆heteroalkyl.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁₂ is hydrogen. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁₂ is halogen. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁₂ is C₁-C₆alkyl. In someembodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₂ is—CH₃.

In some embodiments, provided herein is a compound of Formula (Ia), or apharmaceutically acceptable salt or solvate thereof:

wherein:

L₁ is a bond or C₁-C₆alkyl;

L₂ is C₁-C₆alkyl;

R₁ is C₁-C₉alkyl, C₃-C₆cycloalkyl, or C₂-C₉heteroaryl, whereinC₁-C₉alkyl, C₃-C₆cycloalkyl, or C₂-C₉heteroaryl are optionallysubstituted with 1, 2, or 3 R₅;

R₂ is —C(═O)OR₆;

each R₅ is independently selected from halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆heteroalkyl, —OR₇, —N(R₇)₂, —CN, —C(═O)R₈,—C(═O)OR₇, —C(═O)N(R₇)₂, —NR₇C(═O)R₈, —NR₇S(═O)₂R₈, —S(═O)₂R₈, and—S(═O)₂N(R₇)₂;

R₆ is C₂-C₉heterocycloalkyl substituted with 2 groups selected fromC₁-C₆alkyl and —C(═O)OR₁₃;

each R₇ is independently selected from hydrogen, C₁-C₆alkyl,C₂-C₆alkenyl, C₁-C₆haloalkyl, and C₁-C₆heteroalkyl;

each R₈ is independently selected from C₁-C₆alkyl, C₂-C₆alkenyl,C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, and C₂-C₉heterocycloalkyl; and

each R₁₃ is independently selected from hydrogen and C₁-C₆alkyl.

In some embodiments, provided herein is a compound of Formula (Ia), or apharmaceutically acceptable salt or solvate thereof, wherein L₁ isC₁-C₆alkyl. In some embodiments, provided herein is a compound ofFormula (Ia), or a pharmaceutically acceptable salt or solvate thereof,wherein L₁ is —CH₂—. In some embodiments, provided herein is a compoundof Formula (Ia), or a pharmaceutically acceptable salt or solvatethereof, wherein L₁ is —CH₂CH₂—. In some embodiments, provided herein isa compound of Formula (Ia), or a pharmaceutically acceptable salt orsolvate thereof, wherein L₁ is a bond.

In some embodiments, provided herein is a compound of Formula (Ia), or apharmaceutically acceptable salt or solvate thereof, wherein R₁ isC₁-C₉alkyl optionally substituted with 1, 2, or 3 R₅. In someembodiments, provided herein is a compound of Formula (Ia), or apharmaceutically acceptable salt or solvate thereof, wherein R₁ isC₃-C₉alkyl optionally substituted with 1, 2, or 3 R₅. In someembodiments, provided herein is a compound of Formula (Ia), or apharmaceutically acceptable salt or solvate thereof, wherein R₁ isunsubstituted C₁-C₉alkyl. In some embodiments, provided herein is acompound of Formula (Ia), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₁ is unsubstituted C₃-C₉alkyl. In someembodiments, provided herein is a compound of Formula (Ia), or apharmaceutically acceptable salt or solvate thereof, wherein R₁ isC₃-C₆cycloalkyl optionally substituted with 1, 2, or 3 R₅. In someembodiments, provided herein is a compound of Formula (Ia), or apharmaceutically acceptable salt or solvate thereof, wherein R₁ isC₃-C₆cycloalkyl optionally substituted with 1, 2, or 3 R₅, wherein eachR₅ is independently selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl,—OR₇, and —N(R₇)₂. In some embodiments, provided herein is a compound ofFormula (Ia), or a pharmaceutically acceptable salt or solvate thereof,wherein R₁ is C₃-C₆cycloalkyl optionally substituted with 1, 2, or 3 R₅,wherein each R₅ is independently selected from halogen and C₁-C₆alkyl.In some embodiments, provided herein is a compound of Formula (Ia), or apharmaceutically acceptable salt or solvate thereof, wherein R₁ isunsubstituted C₃-C₆cycloalkyl. In some embodiments, provided herein is acompound of Formula (Ia), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₁ is C₂-C₉heteroaryl optionally substitutedwith 1, 2, or 3 R₅. In some embodiments, provided herein is a compoundof Formula (Ia), or a pharmaceutically acceptable salt or solvatethereof, wherein R₁ is C₂-C₉heteroaryl optionally substituted with 1, 2,or 3 R₅, wherein each R₅ is independently selected from halogen,C₁-C₆alkyl, C₁-C₆haloalkyl, —OR₇, and —N(R₇)₂. In some embodiments,provided herein is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁ is C₂-C₉heteroaryloptionally substituted with 1, 2, or 3 R₅, wherein each R₅ isindependently selected from halogen and C₁-C₆alkyl. In some embodiments,provided herein is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁ is unsubstitutedC₂-C₉heteroaryl. In some embodiments, provided herein is a compound ofFormula (Ia), or a pharmaceutically acceptable salt or solvate thereof,wherein C₂-C₉heteroaryl is selected from oxazolyl, thiazolyl, pyrazolyl,furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl.

In some embodiments, provided herein is a compound of Formula (Ia), or apharmaceutically acceptable salt or solvate thereof, wherein L₂ is—CH₂—. In some embodiments, provided herein is a compound of Formula(Ia), or a pharmaceutically acceptable salt or solvate thereof, whereinL₂ is —CH₂CH₂—. In some embodiments, provided herein is a compound ofFormula (Ia), or a pharmaceutically acceptable salt or solvate thereof,wherein L₂ is —CH₂CH₂CH₂—.

In some embodiments, provided herein is a compound of Formula (Ia), or apharmaceutically acceptable salt or solvate thereof, wherein R₂ is—C(═O)OR₆ and R₆ is C₂-C₉heterocycloalkyl substituted 2 groups selectedfrom C₁-C₆alkyl and —C(═O)OR₁₃, wherein one group is C₁-C₆alkyl and onegroup is —C(═O)OR₁₃. In some embodiments is a compound of Formula (Ia),or a pharmaceutically acceptable salt or solvate thereof, wherein R₆ isselected from piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl,and pyrrolidinyl, wherein piperidinyl, piperazinyl, morpholinyl,tetrahydrofuranyl, and pyrrolidinyl are substituted with 2 groupsselected from C₁-C₆alkyl and —C(═O)OR₁₃, wherein one group is C₁-C₆alkyland one group is —C(═O)OR₁₃. In some embodiments is a compound ofFormula (Ia), or a pharmaceutically acceptable salt or solvate thereof,wherein R₆ is pyrrolidinyl substituted with 2 groups selected fromC₁-C₆alkyl and —C(═O)OR₁₃, wherein one group is C₁-C₆alkyl and one groupis —C(═O)OR₁₃. In some embodiments is a compound of Formula (Ia), or apharmaceutically acceptable salt or solvate thereof, wherein R₆ ispiperidinyl substituted with 2 groups selected from C₁-C₆alkyl and—C(═O)OR₁₃, wherein one group is C₁-C₆alkyl and one group is —C(═O)OR₁₃.In some embodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₆ is morpholinylsubstituted with 2 groups selected from C₁-C₆alkyl and —C(═O)OR₁₃,wherein one group is C₁-C₆alkyl and one group is —C(═O)OR₁₃. In someembodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₆ is piperazinylsubstituted with 2 groups selected from C₁-C₆alkyl and —C(═O)OR₁₃,wherein one group is C₁-C₆alkyl and one group is —C(═O)OR₁₃. In someembodiments is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₆ is tetrahydrofuranylsubstituted with 2 groups selected from C₁-C₆alkyl and —C(═O)OR₁₃,wherein one group is C₁-C₆alkyl and one group is —C(═O)OR₁₃.

In some embodiments, provided herein is a compound of Formula (Ia), or apharmaceutically acceptable salt or solvate thereof, wherein R₁₃ isC₁-C₆alkyl. In some embodiments, provided herein is a compound ofFormula (Ia), or a pharmaceutically acceptable salt or solvate thereof,wherein R₁₃ is —CH₃. In some embodiments, provided herein is a compoundof Formula (Ia), or a pharmaceutically acceptable salt or solvatethereof, wherein R₁₃ is —CH₂CH₃. In some embodiments, provided herein isa compound of Formula (Ia), or a pharmaceutically acceptable salt orsolvate thereof, wherein R₁₃ is —C(H)(CH₃)₂. In some embodiments,provided herein is a compound of Formula (Ia), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁₃ is hydrogen.

In some embodiments, provided herein is a compound selected from:

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, provided herein is a compound selected from:

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the compounds provided herein have IC₅₀s of aboutor less than 50 nM in the JAK/TYK2 assay. In some embodiments, thecompounds provided herein have IC₅₀s of about or less than 100 nM in theJAK/TYK2 assay. In some embodiments, the compounds provided herein haveIC₅₀s of about 10 nM or less, about 20 nM or less, about 25 nM or less,about 50 nM or less, about 100 nM or less, about 250 nM or less, orabout 500 nM or less in the JAK/TYK2 assay. In another embodiment, thecompounds provided herein inhibit JAK1 selectively over JAK2, JAK3, andTYK2. In another embodiment, the compounds provided herein inhibit JAK2selectively over JAK1, JAK3, and TYK2. In another embodiment, thecompounds provided herein inhibit JAK3 selectively over JAK1, JAK2, andTYK2. In another embodiment, the compounds provided herein inhibit TYK2selectively over JAK1, JAK2, and JAK3. In another embodiment, thecompounds provided herein inhibit JAK1 and JAK2 selectively over JAK3and TYK2. In another embodiment, the compounds provided herein inhibitJAK1 and JAK3 selectively over JAK2 and TYK2. In another embodiment, thecompounds provided herein inhibit JAK1 and TYK2 selectively over JAK2and JAK3. In another embodiment, the compounds provided herein inhibitJAK2 and JAK3 selectively over JAK1 and TYK2. In another embodiment, thecompounds provided herein inhibit JAK2 and TYK2 selectively over JAK1and JAK3. In another embodiment, the compounds provided herein inhibitJAK3 and TYK2 selectively over JAK1 and JAK2. In another embodiment, thecompounds provided herein inhibit JAK1, JAK2, and JAK3 selectively overTYK2. In another embodiment, the compounds provided herein inhibit JAK1,JAK2, and TYK2 selectively over JAK3. In another embodiment, thecompounds provided herein inhibit JAK1, JAK3, and TYK2 selectively overJAK2. In another embodiment, the compounds provided herein inhibit JAK2,JAK3, and TYK2 selectively over JAK1.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof can be chosen by one skilled in the field toprovide stable moieties and compounds.

In some embodiments, the therapeutic agent(s) (e.g. compound of Formula(I′), (Ia′), (I), or (Ia)) is present in the pharmaceutical compositionas a pharmaceutically acceptable salt. In some embodiments, any compounddescribed above is suitable for any method or composition describedherein.

Further Forms of Compounds Disclosed Herein Isomers

Furthermore, in some embodiments, the compounds described herein existas geometric isomers. In some embodiments, the compounds describedherein possess one or more double bonds. The compounds presented hereininclude all cis, trans, syn, anti, entgegen (E), and zusammen (Z)isomers as well as the corresponding mixtures thereof. In somesituations, compounds exist as tautomers. The compounds described hereininclude all possible tautomers within the formulas described herein. Insome situations, the compounds described herein possess one or morechiral centers and each center exists in the R configuration or Sconfiguration. The compounds described herein include alldiastereomeric, enantiomeric, and epimeric forms as well as thecorresponding mixtures thereof. In additional embodiments of thecompounds and methods provided herein, mixtures of enantiomers and/ordiastereoisomers, resulting from a single preparative step, combination,or interconversion, are useful for the applications described herein. Insome embodiments, the compounds described herein are prepared asoptically pure enantiomers by chiral chromatographic resolution of theracemic mixture. In some embodiments, the compounds described herein areprepared as their individual stereoisomers by reacting a racemic mixtureof the compound with an optically active resolving agent to form a pairof diastereoisomeric compounds, separating the diastereomers, andrecovering the optically pure enantiomers. In some embodiments,dissociable complexes are preferred (e.g., crystalline diastereomericsalts). In some embodiments, the diastereomers have distinct physicalproperties (e.g., melting points, boiling points, solubilities,reactivity, etc.) and are separated by taking advantage of thesedissimilarities. In some embodiments, the diastereomers are separated bychiral chromatography, or preferably, by separation/resolutiontechniques based upon differences in solubility. In some embodiments,the optically pure enantiomer is then recovered, along with theresolving agent, by any practical means that does not result inracemization.

Labeled Compounds

In some embodiments, the compounds described herein exist in theirisotopically-labeled forms. In some embodiments, the methods disclosedherein include methods of treating diseases by administering suchisotopically-labeled compounds. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch isotopically-labeled compounds as pharmaceutical compositions.Thus, in some embodiments, the compounds disclosed herein includeisotopically-labeled compounds, which are identical to those recitedherein, but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number usually found in nature. Examples of isotopes that areincorporated into compounds described herein include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, andchloride, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²p, ³⁵S, ¹⁸F,and ³⁶Cl, respectively. Compounds described herein, and pharmaceuticallyacceptable salts, esters, solvate, hydrates, or derivatives thereofwhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certainisotopically-labeled compounds, for example those into which radioactiveisotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/orsubstrate tissue distribution assays. Tritiated, i. e., ³H andcarbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their easeof preparation and detectability. Further, substitution with heavyisotopes such as deuterium, i.e., ²H, produces certain therapeuticadvantages resulting from greater metabolic stability, for exampleincreased in vivo half-life or reduced dosage requirements. In someembodiments, the isotopically labeled compounds, pharmaceuticallyacceptable salt, ester, solvate, hydrate, or derivative thereof isprepared by any suitable method.

In some embodiments, the compounds described herein are labeled by othermeans, including, but not limited to, the use of chromophores orfluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Pharmaceutically Acceptable Salts

In some embodiments, the compounds described herein exist as theirpharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts as pharmaceutical compositions.

In some embodiments, the compounds described herein possess acidic orbasic groups and therefore react with any of a number of inorganic ororganic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. In some embodiments, these salts areprepared in situ during the final isolation and purification of thecompounds described herein, or by separately reacting a purifiedcompound in its free form with a suitable acid or base, and isolatingthe salt thus formed.

Solvates

In some embodiments, the compounds described herein exist as solvates.In some embodiments are methods of treating diseases by administeringsuch solvates. Further described herein are methods of treating diseasesby administering such solvates as pharmaceutical compositions.

Solvates contain either stoichiometric or non-stoichiometric amounts ofa solvent, and, in some embodiments, are formed during the process ofcrystallization with pharmaceutically acceptable solvents such as water,ethanol, and the like. Hydrates are formed when the solvent is water, oralcoholates are formed when the solvent is alcohol. Solvates of thecompounds described herein are conveniently prepared or formed duringthe processes described herein. By way of example only, hydrates of thecompounds described herein are conveniently prepared byrecrystallization from an aqueous/organic solvent mixture, using organicsolvents including, but not limited to, dioxane, tetrahydrofuran, orMeOH. In addition, the compounds provided herein exist in unsolvated aswell as solvated forms. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

Synthesis of Compounds

In some embodiments, the synthesis of compounds described herein areaccomplished using means described in the chemical literature, using themethods described herein, or by a combination thereof. In addition,solvents, temperatures and other reaction conditions presented hereinmay vary.

In other embodiments, the starting materials and reagents used for thesynthesis of the compounds described herein are synthesized or areobtained from commercial sources, such as, but not limited to,Sigma-Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics.

In further embodiments, the compounds described herein, and otherrelated compounds having different substituents are synthesized usingtechniques and materials described herein as well as those that arerecognized in the field, such as described, for example, in Fieser andFieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley andSons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989), March, Advanced OrganicChemistry 4^(th), Ed., (Wiley 1992); Carey and Sundberg, AdvancedOrganic Chemistry 4^(th) Ed., Vols. A and B (Plenum 2000, 2001), andGreen and Wuts, Protective Groups in Organic Synthesis 3^(rd) Ed.,(Wiley 1999) (all of which are incorporated by reference for suchdisclosure). General methods for the preparation of compound asdisclosed herein may be derived from reactions and the reactions may bemodified by the use of appropriate reagents and conditions, for theintroduction of the various moieties found in the formulae as providedherein. As a guide the following synthetic methods may be utilized.

Use of Protecting Groups

In the reactions described, it may be necessary to protect reactivefunctional groups, for example hydroxy, amino, imino, thio or carboxygroups, where these are desired in the final product, in order to avoidtheir unwanted participation in reactions. Protecting groups are used toblock some or all of the reactive moieties and prevent such groups fromparticipating in chemical reactions until the protective group isremoved. It is preferred that each protective group be removable by adifferent means. Protective groups that are cleaved under totallydisparate reaction conditions fulfill the requirement of differentialremoval.

Protective groups can be removed by acid, base, reducing conditions(such as, for example, hydrogenolysis), and/or oxidative conditions.Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilylare acid labile and may be used to protect carboxy and hydroxy reactivemoieties in the presence of amino groups protected with Cbz groups,which are removable by hydrogenolysis, and Fmoc groups, which are baselabile. Carboxylic acid and hydroxy reactive moieties may be blockedwith base labile groups such as, but not limited to, methyl, ethyl, andacetyl in the presence of amines blocked with acid labile groups such ast-butyl carbamate or with carbamates that are both acid and base stablebut hydrolytically removable.

Carboxylic acid and hydroxy reactive moieties may also be blocked withhydrolytically removable protective groups such as the benzyl group,while amine groups capable of hydrogen bonding with acids may be blockedwith base labile groups such as Fmoc. Carboxylic acid reactive moietiesmay be protected by conversion to simple ester compounds as exemplifiedherein, which include conversion to alkyl esters, or they may be blockedwith oxidatively-removable protective groups such as2,4-dimethoxybenzyl, while co-existing amino groups may be blocked withfluoride labile silyl carbamates.

Allyl blocking groups are useful in the presence of acid- andbase-protecting groups since the former are stable and can besubsequently removed by metal or pi-acid catalysts. For example, anallyl-blocked carboxylic acid can be deprotected with a Pd⁰-catalyzedreaction in the presence of acid labile t-butyl carbamate or base-labileacetate amine protecting groups. Yet another form of protecting group isa resin to which a compound or intermediate may be attached. As long asthe residue is attached to the resin, that functional group is blockedand cannot react. Once released from the resin, the functional group isavailable to react.

Typically blocking/protecting groups may be selected from:

Other protecting groups, plus a detailed description of techniquesapplicable to the creation of protecting groups and their removal aredescribed in Greene and Wuts, Protective Groups in Organic Synthesis,3rd Ed., John Wiley & Sons, New York, N.Y., 1999, and Kocienski,Protective Groups, Thieme Verlag, New York, N.Y., 1994, which areincorporated herein by reference for such disclosure).

Methods of Treatment and Prevention

In some embodiments is a method of treating an inflammatory orautoimmune disease in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of acompound Formula (I′), (Ia′), (I), or (Ia), or a pharmaceuticallyacceptable salt or solvate thereof. In some embodiments is a method oftreating an inflammatory disease in a patient in need thereof,comprising administering to the patient a therapeutically effectiveamount of a compound Formula (I′), (Ia′), (I), or (Ia), or apharmaceutically acceptable salt or solvate thereof. In some embodimentsis a method of treating an autoimmune disease in a patient in needthereof, comprising administering to the patient a therapeuticallyeffective amount of a compound Formula (I′), (Ia′), (I), or (Ia), or apharmaceutically acceptable salt or solvate thereof. In some embodimentsis a method of treating an inflammatory or autoimmune disease in apatient in need thereof, comprising administering to the patient atherapeutically effective amount of a compound Formula (I′), (Ia′), (I),or (Ia), or a pharmaceutically acceptable salt or solvate thereof,wherein the disease, disorder, or condition is selected from rheumatoidarthritis, multiple sclerosis, psoriasis, lupus, intestinal boweldisease, Crohn's disease, ulcerative colitis, ankylosing spondylitis,vitiligo, and atopic dermatitis. In some embodiments is a method oftreating an inflammatory or autoimmune disease in a patient in needthereof, comprising administering to the patient a therapeuticallyeffective amount of a compound Formula (I′), (Ia′), (I), or (Ia), or apharmaceutically acceptable salt or solvate thereof, wherein thedisease, disorder, or condition is rheumatoid arthritis. In someembodiments is a method of treating an inflammatory or autoimmunedisease in a patient in need thereof, comprising administering to thepatient a therapeutically effective amount of a compound Formula (I′),(Ia′), (I), or (Ia), or a pharmaceutically acceptable salt or solvatethereof, wherein the disease, disorder, or condition is multiplesclerosis. In some embodiments is a method of treating an inflammatoryor autoimmune disease in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of acompound Formula (I′), (Ia′), (I), or (Ia), or a pharmaceuticallyacceptable salt or solvate thereof, wherein the disease, disorder, orcondition is psoriasis. In some embodiments is a method of treating aninflammatory or autoimmune disease in a patient in need thereof,comprising administering to the patient a therapeutically effectiveamount of a compound Formula (I′), (Ia′), (I), or (Ia), or apharmaceutically acceptable salt or solvate thereof, wherein thedisease, disorder, or condition is lupus. In some embodiments is amethod of treating an inflammatory or autoimmune disease in a patient inneed thereof, comprising administering to the patient a therapeuticallyeffective amount of a compound Formula (I′), (Ia′), (I), or (Ia), or apharmaceutically acceptable salt or solvate thereof, wherein thedisease, disorder, or condition is intestinal bowel disease. In someembodiments is a method of treating an inflammatory or autoimmunedisease in a patient in need thereof, comprising administering to thepatient a therapeutically effective amount of a compound Formula (I′),(Ia′), (I), or (Ia), or a pharmaceutically acceptable salt or solvatethereof, wherein the disease, disorder, or condition is Crohn's disease.In some embodiments is a method of treating an inflammatory orautoimmune disease in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of acompound Formula (I′), (Ia′), (I), or (Ia), or a pharmaceuticallyacceptable salt or solvate thereof, wherein the disease, disorder, orcondition is ulcerative colitis. In some embodiments is a method oftreating an inflammatory or autoimmune disease in a patient in needthereof, comprising administering to the patient a therapeuticallyeffective amount of a compound Formula (I′), (Ia′), (I), or (Ia), or apharmaceutically acceptable salt or solvate thereof, wherein thedisease, disorder, or condition is ankylosing spondylitis. In someembodiments is a method of treating an inflammatory or autoimmunedisease in a patient in need thereof, comprising administering to thepatient a therapeutically effective amount of a compound Formula (I′),(Ia′), (I), or (Ia), or a pharmaceutically acceptable salt or solvatethereof, wherein the disease, disorder, or condition is vitiligo. Insome embodiments is a method of treating an inflammatory or autoimmunedisease in a patient in need thereof, comprising administering to thepatient a therapeutically effective amount of a compound Formula (I′),(Ia′), (I), or (Ia), or a pharmaceutically acceptable salt or solvatethereof, wherein the disease, disorder, or condition is atopicdermatitis.

Pharmaceutical Compositions and Methods of Administration

JAK inhibitors described herein are administered to subjects in abiologically compatible form suitable for administration to treat orprevent diseases, disorders or conditions. Administration of JAKinhibitors as described herein can be in any pharmacological formincluding a therapeutically effective amount of a JAK inhibitor alone orin combination with a pharmaceutically acceptable carrier.

In certain embodiments, the compounds described herein are administeredas a pure chemical. In other embodiments, the compounds described hereinare combined with a pharmaceutically suitable or acceptable carrier(also referred to herein as a pharmaceutically suitable (or acceptable)excipient, physiologically suitable (or acceptable) excipient, orphysiologically suitable (or acceptable) carrier) selected on the basisof a chosen route of administration and standard pharmaceutical practiceas described, for example, in Remington: The Science and Practice ofPharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, Pa. (2005)).

Accordingly, provided herein is a pharmaceutical composition comprisingat least one compound described herein, or a pharmaceutically acceptablesalt, together with one or more pharmaceutically acceptable carriers.The carrier(s) (or excipient(s)) is acceptable or suitable if thecarrier is compatible with the other ingredients of the composition andnot deleterious to the recipient (i.e., the subject) of the composition.

In some embodiments is a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of Formula (I′),(Ia′), (I), or (Ia), or a pharmaceutically acceptable salt or solvatethereof. In some embodiments is a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and a compound of Formula (I′), ora pharmaceutically acceptable salt or solvate thereof. In someembodiments is a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of Formula (Ia′), ora pharmaceutically acceptable salt or solvate thereof. In someembodiments is a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof. In some embodimentsis a pharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound of Formula (Ia), or a pharmaceutically acceptablesalt or solvate thereof.

Another embodiment provides a pharmaceutical composition consistingessentially of a pharmaceutically acceptable carrier and a compound ofFormula (I′), (Ia′), (I), or (Ia), or a pharmaceutically acceptable saltor solvate thereof. In some embodiments is a pharmaceutical compositionconsisting essentially of a pharmaceutically acceptable carrier and acompound of Formula (I), or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments is a pharmaceutical compositionconsisting essentially of a pharmaceutically acceptable carrier and acompound of Formula (Ia), or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments is a pharmaceutical compositionconsisting essentially of a pharmaceutically acceptable carrier and acompound of Formula (I′), or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments is a pharmaceutical compositionconsisting essentially of a pharmaceutically acceptable carrier and acompound of Formula (Ia′), or a pharmaceutically acceptable salt orsolvate thereof.

In certain embodiments, the compound as described herein issubstantially pure, in that it contains less than about 5%, or less thanabout 1%, or less than about 0.1%, of other organic small molecules,such as contaminating intermediates or by-products that are created, forexample, in one or more of the steps of a synthesis method.

These formulations include those suitable for oral, topical, buccal,parenteral (e.g., subcutaneous, intramuscular, intradermal, orintravenous), or aerosol administration.

Exemplary pharmaceutical compositions are used in the form of apharmaceutical preparation, for example, in solid, semisolid or liquidform, which includes one or more of a disclosed compound, as an activeingredient, in a mixture with an organic or inorganic carrier orexcipient suitable for external, enteral or parenteral applications. Insome embodiments, the active ingredient is compounded, for example, withthe usual non-toxic, pharmaceutically acceptable carriers for tablets,pellets, capsules, suppositories, solutions, emulsions, suspensions, andany other form suitable for use. The active object compound is includedin the pharmaceutical composition in an amount sufficient to produce thedesired effect upon the process or condition of the disease.

In some embodiments, JAK inhibitors described herein are administered tosubjects in a biologically compatible form suitable for topicaladministration to treat or prevent dermal diseases, disorders, orconditions. By “biologically compatible form suitable for topicaladministration” is meant a form of the JAK inhibitor to be administeredin which any toxic effects are outweighed by the therapeutic effects ofthe inhibitor. Administration of JAK inhibitors as described herein canbe in any pharmacological form including a therapeutically effectiveamount of a. AK inhibitor alone or in combination with apharmaceutically acceptable carrier.

Topical administration of a JAK inhibitor may be presented in the formof an aerosol, a semi-solid pharmaceutical composition, a powder, or asolution. By the term “a semi-solid composition” is meant an ointment,cream, salve, jelly, or other pharmaceutical composition ofsubstantially similar consistency suitable for application to the skin.Examples of semi-solid compositions are given in Chapter 17 of TheTheory and Practice of Industrial Pharmacy, Lachman, Lieberman andKanig, published by Lea and Febiger (1970) and in Chapter 67 ofRemington's Pharmaceutical Sciences, 15th Edition (1975) published byMack Publishing Company.

Dermal or skin patches are another method for transdermal delivery ofthe therapeutic or pharmaceutical compositions described herein. Patchescan provide an absorption enhancer such as DMSO to increase theabsorption of the compounds. Patches can include those that control therate of drug delivery to the skin. Patches may provide a variety ofdosing systems including a reservoir system or a monolithic system,respectively. The reservoir design may, for example, have four layers:the adhesive layer that directly contacts the skin, the controlmembrane, which controls the diffusion of drug molecules, the reservoirof drug molecules, and a water-resistant backing. Such a design deliversuniform amounts of the drug over a specified time period, the rate ofdelivery has to be less than the saturation limit of different types ofskin. The monolithic design, for example, typically has only threelayers: the adhesive layer, a polymer matrix containing the compound,and a water-proof backing. This design brings a saturating amount ofdrug to the skin. Thereby, delivery is controlled by the skin. As thedrug amount decreases in the patch to below the saturating level, thedelivery rate falls.

In one embodiment, the topical composition may, for example, take theform of hydrogel based on polyacrylic acid or polyacrylamide; as anointment, for example with polyethyleneglycol (PEG) as the carrier, likethe standard ointment DAB 8 (50% PEG 300, 50% PEG 1500); or as anemulsion, especially a microemulsion based on water-in-oil oroil-in-water, optionally with added liposomes. Suitable permeationaccelerators (entraining agents) include sulphoxide derivatives such asdimethylsulphoxide (DMSO) or decylmethylsulphoxide (decyl-MSO) andtranscutol (diethyleneglycolmonoethylether) or cyclodextrin; as well aspyrrolidones, for example 2-pyrrolidone, N-methyl-2-pyrrolidone,2-pyrrolidone-5-carboxylic acid, or the biodegradableN-(2-hydroxyethyl)-2-pyrrolidone and the fatty acid esters thereof; ureaderivatives such as dodecylurea, 1,3-didodecylurea, and1,3-diphenylurea; and terpenes, for example D-limonene, menthone,a-terpinol, carvol, limonene oxide, or 1,8-cineol.

Ointments, pastes, creams and gels also can contain excipients, such asstarch, tragacanth, cellulose derivatives, polyethylene glycols,silicones, bentonites, silicic acid, and talc, or mixtures thereof.Powders and sprays also can contain excipients such as lactose, talc,silicic acid, aluminum hydroxide, calcium silicates and polyamidepowder, or mixtures of these substances. Solutions of nanocrystallineantimicrobial metals can be converted into aerosols or sprays by any ofthe known means routinely used for making aerosol pharmaceuticals. Ingeneral, such methods comprise pressurizing or providing a means forpressurizing a container of the solution, usually with an inert carriergas, and passing the pressurized gas through a small orifice. Sprays canadditionally contain customary propellants, such achlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, suchas butane and propane.

The carrier can also contain other pharmaceutically-acceptableexcipients for modifying or maintaining the pH, osmolarity, viscosity,clarity, color, sterility, stability, rate of dissolution, or odor ofthe formulation. The anti-skin aging compositions can also furthercomprise antioxidants, sun screens, natural retinoids (e.g., retinol),and other additives commonly found in skin treatment compositions.

In some embodiments for preparing solid compositions such as tablets,the principal active ingredient is mixed with a pharmaceutical carrier,e.g., conventional tableting ingredients such as corn starch, lactose,sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalciumphosphate or gums, and other pharmaceutical diluents, e.g., water, toform a solid preformulation composition containing a homogeneous mixtureof a disclosed compound or a non-toxic pharmaceutically acceptable saltthereof. When referring to these preformulation compositions ashomogeneous, it is meant that the active ingredient is dispersed evenlythroughout the composition so that the composition is readily subdividedinto equally effective unit dosage forms such as tablets, pills andcapsules.

In solid dosage forms for oral administration (capsules, tablets, pills,dragees, powders, granules and the like), the subject composition ismixed with one or more pharmaceutically acceptable carriers, such assodium citrate or dicalcium phosphate, and/or any of the following: (1)fillers or extenders, such as starches, cellulose, microcrystallinecellulose, silicified microcrystalline cellulose, lactose, sucrose,glucose, mannitol, and/or silicic acid; (2) binders, such as, forexample, carboxymethylcellulose, hypromellose, alginates, gelatin,polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such asglycerol; (4) disintegrating agents, such as crospovidone,croscarmellose sodium, sodium starch glycolate, agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,and sodium carbonate; (5) solution retarding agents, such as paraffin;(6) absorption accelerators, such as quaternary ammonium compounds; (7)wetting agents, such as, for example, docusate sodium, cetyl alcohol andglycerol monostearate; (8) absorbents, such as kaolin and bentoniteclay; (9) lubricants, such a talc, calcium stearate, magnesium stearate,solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof;and (10) coloring agents. In the case of capsules, tablets and pills, insome embodiments, the compositions comprise buffering agents. In someembodiments, solid compositions of a similar type are also employed asfillers in soft and hard-filled gelatin capsules using such excipientsas lactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

In some embodiments, a tablet is made by compression or molding,optionally with one or more accessory ingredients. In some embodiments,compressed tablets are prepared using binder (for example, gelatin orhydroxypropylmethyl cellulose), lubricant, inert diluent, preservative,disintegrant (for example, sodium starch glycolate or cross-linkedsodium carboxymethyl cellulose), surface-active or dispersing agent. Insome embodiments, molded tablets are made by molding in a suitablemachine a mixture of the subject composition moistened with an inertliquid diluent. In some embodiments, tablets, and other solid dosageforms, such as dragees, capsules, pills and granules, are scored orprepared with coatings and shells, such as enteric coatings and othercoatings.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. Liquid dosage forms for oraladministration include pharmaceutically acceptable emulsions,microemulsions, solutions, suspensions, syrups and elixirs. In additionto the subject composition, in some embodiments, the liquid dosage formscontain inert diluents, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, cyclodextrins and mixtures thereof.

In some embodiments, suspensions, in addition to the subjectcomposition, contain suspending agents as, for example, ethoxylatedisostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters,microcrystalline cellulose, aluminum metahydroxide, bentonite,agar-agar, and tragacanth, and mixtures thereof.

In some embodiments, powders and sprays contain, in addition to asubject composition, excipients such as lactose, talc, silicic acid,aluminum hydroxide, calcium silicates, and polyamide powder, or mixturesof these substances. In some embodiments, sprays additionally containcustomary propellants, such as chlorofluorohydrocarbons and volatileunsubstituted hydrocarbons, such as butane and propane.

Compositions and compounds disclosed herein alternatively areadministered by aerosol. This is accomplished by preparing an aqueousaerosol, liposomal preparation, or solid particles containing thecompound. In some embodiments, a non-aqueous (e.g., fluorocarbonpropellant) suspension is used. In some embodiments, sonic nebulizersare used because they minimize exposing the agent to shear, whichresults in degradation of the compounds contained in the subjectcompositions.

Ordinarily, an aqueous aerosol is made by formulating an aqueoussolution or suspension of a subject composition together withconventional pharmaceutically acceptable carriers and stabilizers. Thecarriers and stabilizers vary with the requirements of the particularsubject composition, but typically include non-ionic surfactants(Tweens, Pluronics, or polyethylene glycol), innocuous proteins likeserum albumin, sorbitan esters, oleic acid, lecithin, amino acids suchas glycine, buffers, salts, sugars, or sugar alcohols. Aerosolsgenerally are prepared from isotonic solutions.

Pharmaceutical compositions suitable for parenteral administrationcomprise a subject composition in combination with one or morepharmaceutically-acceptable sterile isotonic aqueous or non-aqueoussolutions, dispersions, suspensions or emulsions, or sterile powderswhich are reconstituted into sterile injectable solutions or dispersionsjust prior to use, which, in some embodiments, contain antioxidants,buffers, bacteriostats, solutes which render the formulation isotonicwith the blood of the intended recipient, or suspending or thickeningagents.

Examples of suitable aqueous and non-aqueous carriers which are employedin the pharmaceutical compositions include water, ethanol, polyols (suchas glycerol, propylene glycol, polyethylene glycol, and the like), andsuitable mixtures thereof, vegetable oils, such as olive oil, andinjectable organic esters, such as ethyl oleate and cyclodextrins.Proper fluidity is maintained, for example, by the use of coatingmaterials, such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants

The dose of the composition comprising at least one compound describedherein differs, depending upon the patient's (e.g., human) condition,that is, stage of the disease, general health status, age, and otherfactors.

Pharmaceutical compositions are administered in a manner appropriate tothe disease to be treated (or prevented). An appropriate dose and asuitable duration and frequency of administration will be determined bysuch factors as the condition of the patient, the type and severity ofthe patient's disease, the particular form of the active ingredient, andthe method of administration. In general, an appropriate dose andtreatment regimen provides the composition(s) in an amount sufficient toprovide therapeutic and/or prophylactic benefit (e.g., an improvedclinical outcome, such as more frequent complete or partial remissions,or longer disease-free and/or overall survival, or a lessening ofsymptom severity). Optimal doses are generally determined usingexperimental models and/or clinical trials. In some embodiments, theoptimal dose depends upon the body mass, weight, or blood volume of thepatient.

Oral doses typically range from about 1.0 mg to about 1000 mg, one tofour times, or more, per day.

Dose administration can be repeated depending upon the pharmacokineticparameters of the dosage formulation and the route of administrationused.

It is especially advantageous to formulate compositions in dosage unitform for ease of administration and uniformity of dosage. Dosage unitform as used herein refers to physically discrete units suited asunitary dosages for the mammalian subjects to be treated; each unitcontaining a predetermined quantity of active compound calculated toproduce the desired therapeutic effect in association with the requiredpharmaceutical carrier. The specification for the dosage unit forms aredictated by and directly dependent on (a) the unique characteristics ofthe JAK inhibitor and the particular therapeutic effect to be achievedand (b) the limitations inherent in the art of compounding such anactive compound for the treatment of sensitivity in individuals. Thespecific dose can be readily calculated by one of ordinary skill in theart, e.g., according to the approximate body weight or body surface areaof the patient or the volume of body space to be occupied. The dose willalso be calculated dependent upon the particular route of administrationselected. Further refinement of the calculations necessary to determinethe appropriate dosage for treatment is routinely made by those ofordinary skill in the art. Such calculations can be made without undueexperimentation by one skilled in the art in light of the JAK inhibitoractivities disclosed herein in assay preparations of target cells. Exactdosages are determined in conjunction with standard dose-responsestudies. It will be understood that the amount of the compositionactually administered will be determined by a practitioner, in the lightof the relevant circumstances including the condition or conditions tobe treated, the choice of composition to be administered, the age,weight, and response of the individual patient, the severity of thepatient's symptoms, and the chosen route of administration.

Toxicity and therapeutic efficacy of such JAK inhibitors can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, for example, for determining the LD₅₀ (the doselethal to 50% of the population) and the ED₅₀ (the dose therapeuticallyeffective in 50% of the population). The dose ratio between toxic andtherapeutic effects is the therapeutic index and it can be expressed asthe ratio LD₅₀/ED₅₀. JAK inhibitors that exhibit large therapeuticindices are preferred. While JAK inhibitors that exhibit toxic sideeffects may be used, care should be taken to design a delivery systemthat targets such inhibitors to the site of affected tissue in order tominimize potential damage to uninfected cells and, thereby, reduce sideeffects.

The data obtained from the cell culture assays and animal studies can beused in formulating a range of dosage for use in humans. The dosage ofsuch JAK inhibitors lies preferably within a range of circulatingconcentrations that include the ED₅₀ with little or no toxicity. Thedosage may vary within this range depending upon the dosage formemployed and the route of administration utilized. For any JAK inhibitorused in a method described herein, the therapeutically effective dosecan be estimated initially from cell culture assays. A dose may beformulated in animal models to achieve a circulating plasmaconcentration range that includes the IC₅₀ (i.e., the concentration ofJAK inhibitor that achieves a half-maximal inhibition of symptoms) asdetermined in cell culture. Such information can be used to moreaccurately determine useful doses in humans. Levels in plasma may bemeasured, for example, by high performance liquid chromatography.

EXAMPLES

The following examples are offered for purposes of illustration and arenot intended to limit the scope of the claims provided herein. Allliterature citations in these examples and throughout this specificationare incorporated herein by references for all legal purposes to beserved thereby. The starting materials and reagents used for thesynthesis of the compounds described herein may be synthesized or can beobtained from commercial sources, such as, but not limited to,Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.

Standard abbreviations and acronyms as defined in J. Org. Chem. 200772(1): 23A-24A are used herein. Other abbreviations and acronyms usedherein are as follows:

-   -   AcOH acetic acid    -   DMF dimethylformamide    -   DMP Dess-Martin periodinane    -   dppf (diphenylphosphino)ferrocene    -   EtOAc ethyl acetate    -   EtOH ethanol    -   eq equivalent    -   HBTU N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium        hexafluorophosphate    -   LC-MS liquid chromatography-mass spectrometry    -   MeOH methanol    -   TEA triethylamine    -   rt room temperature

General Synthetic Scheme:

General Procedure

To a solution of 2 (1.0 eq) in DMF was added Cs₂CO₃ (2.5 eq). Themixture was stirred at room temperature for 5 mins under N₂. 1 (1.5 eq)was then added to the reaction mixture. The resulting mixture was heatedat 50° C. to 90° C. to afford 3.

3 (1.0 eq) and 4 (HCl salt, 1.4 eq) were combined in dry EtOH. Themixture was heated at 120° C. in a sealed-tube for 20 hrs to 48 hrs toprovide 5.

Example A: Synthesis of Intermediate 1

The alcohol was dissolved in DCM and pyridine (5 eq). To the solutionwas added MsCl (1.5 eq) or TsCl (1.5 eq) at 0° C. The reaction mixturewas stirred at RT for 2 hrs to afford 1.

Example B: Synthesis of Intermediates 4-a, 4-b, 4-c, 4-d, 4-e

Synthesis of 4-a

To a solution of 4-nitropyrazole (1.13 g, 1.0 eq) in dry DMF (15 mL) wasadded Cs₂CO₃ (8.13 g, 2.5 eq). The mixture was stirred at RT for 30 minsunder N₂, and then bromoacetate (2 g, 1.2 eq) was added into reaction.The resulting mixture was stirred at RT overnight. The reaction mixturewas diluted with 50 mL ethyl acetate and 10 mL hexane. The inorganic wasremoved by filtration. The filtrate was washed with 3×30 mL water andbrine. The crude was purified on ISCO silica gel to afford 6 (1.65 g,yield 83%) as a white solid.

To a solution of Intermediate 6 (1.65 g) in ethylacetate (40 mL) wasadded Pd/C (Pd on Carbon, 165 mg). The mixture was hydrogenated at 30psi for 2 hrs. The catalyst was removed by filtration. To the ethylacetate solution was added 2N HCl in ether (10 mL), and stirred at RTfor 5 mins. Removal solvent in vacuo gave 4-a as HCl salt (1.5 g).

4-c, 4-d, and 4-e were prepared in a similar manner as described for4-a.

Synthesis of Intermediate 4-b

NaH (60% in mineral oil, 0.48 g, 1.0 eq) was suspended into dry THE (15mL) at 0° C. under N₂. A solution of 3-aminopyrazole (1.0 g, 1.0 eq) indry THE (5 mL) was added dropwise at 0° C. The mixture was stirred at 0°C. for 30 mins. Bromoacetate (2.0 g, 1.0 eq) was added dropwise. Theresulting mixture was stirred at 0° C. for 1 hr and then at roomtemperature overnight. The precipitate was removed by filtration, thefiltrate was concentrated in vacuo to afford an oil which was purifiedon ISCO silica gel column directly to afford 7 (0.28 g). 7 was treatedwith 2N HCl in ether to afford 4-b as an HCl salt.

Example 1: Synthesis of ethyl(2S,4R)-4-(2-(4-((7-((S)-2-ethyl-3-methylbutyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)acetoxy)-1-methylpyrrolidine-2-carboxylate(133)

4,4-Dimethylaminopyridine (0.5 g) and triethylamine (8.8 mL) indichloromethane (20 mL) were added to a solution of(S)-(−)-4-benzyl-2-oxazolidinone (9) (7 g, 40 mmol) in dichloromethane(100 mL). Isovaleroyl chloride (5 g, 41.4 mmol) in dichloromethane (15mL) was added to the previously prepared mixture and cooled to 0° C.keeping the internal temperature below 10° C. The reaction mixture wasstirred for 30 minutes at 10° C. Water (100 mL) was added and the phaseswere separated. The organic phase was washed with a saturated aqueousNaHCO₃ solution (50 mL), water (50 mL), HCl (2N, 30 mL), water (50 mL)and brine (50 mL), dried over Na₂SO₄ and evaporated to dryness to givecompound 10 (9.5 g) as a yellow oil.

To a solution of NaHMDS (6 mL, 6 mmol; 1 M in THF) in anhydrous THE (20mL) was added a solution of compound 10 (1.3 g, 5 mmol) in anhydrous THE(10 mL) at −78° C. under N₂. The mixture was stirred for 1.5 hr at −78°C. and then iodoethane (3.12 g, 20 mmol) was added dropwise. Theresulting mixture was stirred at −78° C. for 2 h and then allowed toreach −5° C. and stirred for 4 h. The mixture was allowed to warm toroom temperature overnight. The reaction was quenched by the addition ofsaturated aqueous NH₄C₁ solution (30 mL) and the product was extractedwith ethyl acetate (3×50 mL). The combined organic layers weresuccessively washed with ice-cold HCl (1 M, 20 mL), saturated aqueousNaHCO₃ solution (2×30 mL), and brine, and then dried over anhydrousNa₂SO₄. The crude mixture was purified by flash chromatography on silicagel to afford compound 11 (0.75 g) as a yellow oil.

A solution of compound 11 (0.87 g, 3 mmol) in THE (15 mL) and H₂O (5 mL)at 0° C. was treated with ˜30% aqueous H₂O₂ solution (2 mL) followed byLiH (0.24 g, 6 mmol) in H₂O (3 mL). The resulting mixture was warmed toroom temperature and stirred for 5 h. The mixture was cooled to 0° C.and 2 M aqueous Na₂SO₃ solution (5 mL) was added. THE was removed underreduced pressure. The aqueous residue was basified with 2 M aqueous NaOHsolution to pH 12-13 and extracted with CH₂C₂ (5×20 mL). The aqueouslayer was cooled to 0° C. and acidified with 10% aqueous HCl solution topH-1. The product was extracted with ethyl acetate (5×20 mL), and thecombined organic layers were dried over anhydrous Na₂SO₄. After removalof the solvent, compound 12 (0.27 g) was obtained as a colorless oil.

Compound 12 (265 mg, 1.0 eq) was dissolved in dry THE (8 mL) and cooledwith ice-water bath under N₂. To the solution was added LAH 1M in THE(6.1 mL, 3.0 mL) dropwise over 5 mins. The resulting mixture was stirredat room temperature overnight. The reaction was quenched with 2N HCl at0° C. (pH˜1) and then extracted with DCM (3×20 mL). The combined DCMlayers were washed with brine and dried over Na₂SO₄ to afford compound13 (232 mg, yield 98%), which was used without further purification.

To a solution of compound 13 (230 mg, 1.0 eq) and DIEA (770 mg, 3.0 eq)in DCM (15 mL) at 0° C. was added MsCl (1.5 eq). The resulting mixturewas stirred at room temperature for 2 hrs. The reaction was diluted withDCM (30 mL), washed with 1N HCl (2×30 mL), water and sat. NaHCO₃. Thecrude mixture was purified on ISCO silica gel column to afford compound14 (276 mg, yield 72%) as a clear oil.

Compound 14 (276 mg, 1.0 eq), 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (218mg, 1.0 eq) and Cs₂CO₃ (1156 mg, 2.5 eq) were combined in dry DMF (10mL). The mixture was heated at 50° C. under N₂ for 15 hrs. The reactionmixture was diluted with ethyl acetate (20 mL) and hexane (30 mL), andthen washed with water (3×30 mL) and brine. The crude mixture waspurified on silica gel column to afford compound 15 (280 mg, yield 78%)as a clear oil.

Compound 15 (500 mgs, 1.0 eq) and ethyl2-(4-amino-1H-pyrazol-1-yl)acetate hydrochloride (4-a) (650 mg, 1.5 eq)were combined in iPrOH (40 mL). The resulting mixture was heated at 125°C. in a sealed-tube for 20 hrs. The solvent was removed in vacuo. Theresidue was dissolved in ethyl acetate (300 mL) and washed with asaturated aqueous NaHCO₃ solution. The crude mixture was purified onISCO silica gel column to afford compound 16 (480 mg, yield 61%).

To a solution of compound 16 (400 mg, 1.0 eq) in THE (30 mL) was added2N NaOH (5 mL). The resulting mixture was heated at 50° C. for 2 hr. Thesolvent was removed in vacuo, the residue was diluted with water (10mL), and adjusted pH˜5 by adding 2N HCl. The precipitated solid wascollected by filtration and washed with DI water (2×5 mL). The solid wasdried in high vacuo to afford compound 17 (288 mg, yield 80%).

Compound 18 (5 g) was dissolved in absolute EtOH (120 mL). To thesolution was bubbled HCl gas for 5 mins at 0° C. The resulting mixturewas heated at 65° C. in a sealed-pressure bottle for 18 hrs. The solventwas removed in vacuo. The residue was suspended in ethyl acetate (100mL) and ice-water (20 mL). The mixture was stirred at 0° C., and the pHwas adjusted to pH 8 by adding a saturated aqueous NaHCO₃ solution. Theorganic phase was separated, and the aqueous was extracted with ethylacetate (2×30 mL). The combined organic was dried over Na₂SO₄ andconcentrated in vacuo to afford 19 (3.0 g), which was used withoutfurther purification.

To a suspension solution of compound 17 (2.0 g, 1.0 eq) in DMF (25 mL)was added DIEA (2.2 g, 3.0 eq). The mixture was stirred at roomtemperature for 5 min to form a clear solution, and then cooled withice-water bath. EDCI (1.94 g, 1.8 eq), HOBT (1.36 g, 1.8 eq), andcompound 19 (1.75 g, 1.8 eq) were added to reaction mixture under N₂.The resulting mixture was stirred at room temperature for 15 hr. Thereaction was diluted with ethylacetate (80 mL) and hexane (20 mL),washed with water (3×50 mL) and brine. The crude mixture was purified onISCO (40 g column) to afford ethyl(2S,4R)-4-(2-(4-((7-((S)-2-ethyl-3-methylbutyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)acetoxy)-1-methylpyrrolidine-2-carboxylate(133) (2.25 g, yield 78%). MS: 512.4 [M+H]⁺.

Compounds 129-132, 134, and 135 were prepared by similar procedures asdescribed in the preceding Example.

Com- MS pound Structure Name [M + H]⁺ 129

1-(dimethylamino) propan-2-yl 2- (4-((7-((S)-2-ethyl-3- methylbutyl)-7H-pyrrolo[2,3-d] pyrimidin-2- yl)amino)-1H- pyrazol-1-yl)acetate 442.4130

1-methylazetidin-3- yl (S)-2-(4-((7- (2-ethyl-3-methylbutyl)-7H-pyrrolo[2,3-d]pyrimidin-2- yl)amino)-1H- pyrazol-1-yl)acetate 426.5 131

methyl (2S,4R)-4- (2-(4-((7-((S)-2- ethyl-3-methylbutyl)-7H-pyrrolo[2,3-d]pyrimidin-2- yl)amino)-1H-pyrazol-1- yl)acetoxy)-1-methylpyrrolidine-2- carboxylate 498.2 132

methyl (2S,4R)- 4-(2-(4-((7-(2- ethylbutyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-1H- pyrazol-1-yl)acetoxy)-1- methylpyrrolidine-2-carboxylate 483.5 134

isopropyl (2S,4R)- 4-(2-(4-((7-((S)- 2-ethyl-3-methylbutyl)-7H-pyrrolo[2,3-d]pyrimidin-2- yl)amino)-1H-pyrazol-1- yl)acetoxy)-1-methylpyrrolidine-2- carboxylate 526.3 135

(2S,4R)-4-(2-(4- ((7-((S)-2-ethyl-3- methylbutyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-1H- pyrazol-1-yl)acetoxy)-1- methylpyrrolidine-2-carboxylic acid 484.7

Example 2: JAK/TYK2 Assay

10 mM test compound stock or 1 mM control compound stock (tofocitinib,ruxolitinib or staurosporine) in DMSO was diluted to 0.4 mM in DMSO. A3-fold series dilution was then performed in DMSO to generate 10different compound concentrations. The assay was carried out in 384-wellwhite plate. 0.5 uL of 40× compound DMSO solution at differentconcentrations was mixed with 10 uL 2× enzyme prepared in reactionbuffer (20 mM HEPES, 10 mM MgCl₂, 0.01% Tween, 1 mM DTT, pH 7.5). 10 uL2× substrate mixture prepared in reaction buffer was then added to startthe reaction. A short spin was done to settle down all solutions to thebottom of the plate. Final concentrations of test compound in thereaction mixture were 10000, 3333, 1111, 370, 123, 41.2, 13.7, 4.57,1.52 and 0.51 nM. Concentrations of control compound were ten timesless. Enzymatic reaction was conducted at 25° C. for 1-2 hours. 10 uL ofKinase Glo Reagents was added to stop the reaction and generate theluminescent signal which was measured using Envision. Luminescencesignal was inversely related to kinase activity. Reaction mixture whichdid not contain enzyme served as negative control. The mixture withoutany compound was the positive control. Final concentration of enzymesand substrates and incubation time are summarized in the table below.

[enz] [ATP] [sub] time JAK1 7.5 nM 2 uM 30 uM (IRS-1) 1 hr JAK2 0.8 nM 2uM  4 uM (pEY) 1 hr JAK3 1.5 nM 2 uM  4 uM (pEY) 1 hr TYK2   9 nM 2 uM30 uM (IRS-1) 1 hr

IC₅₀ values are shown in the table below.

JAK1 JAK2 JAK3 TYK2 Compound (IC₅₀) (IC₅₀) (IC₅₀) (IC₅₀) 129 NT NT NT NT130 NT NT NT NT 131 A A A A 132 A A A A 133 A A A A 134 A B B B 135 B BB B A: IC₅₀ <100 nM; B: IC₅₀ ≥100 nM and <1 uM; NT = not tested

Example 3: JAK1/JAK3: IL-2 Stimulated STAT5 Phosphorylation in PBMCsAssay Human PBMCs: (Precision Biomedicine)

Thaw as per instructions. Thaw frozen PBMCs in 37° C. water bath.Transfer cell suspension to 9 mL of pre-warmed complete media (RPMI+10%FBS+L-Glu+Pen/Strep). Centrifuge at 400×g for 5 min and wash cells with10 mL of complete media. Resuspend pellet for a cell-count of 3×106cells/mL

Compound and Cytokine Treatment

Seed cells into 96-deep well at 80 uL/well based on experimental platelayout. Add 10 μL of (10× conc.) of different concentrations ofcompounds to all wells except controls (unstimulated) and mix it with200 uL multichannel pipet. Add 10 uL of complete RPMI media with same %DMSO in controls. For dilution of compounds and dilution range pleaserefer to appendix. Incubate in 5% CO₂ incubator for 1 hour at 37° C. Add10 μL of (10× conc.) IL-2 (final conc. 50 ng/mL) to each well exceptunstimulated and unstained controls and incubate further for 20 minutesin water bath at 37° C.

Fixation

Add 900 μL of prewarmed 1× Fix/Lyse solution (Appendix) and mix itproperly using 1000 μL multichannel pipet; incubate further on waterbath at 37° C. for 10 minutes. Centrifuge at 800×g for 5 minutes, remove900 uL of supernatant, and add 1000 μL of freshly prepared wash bufferor 1×PBS. Centrifuge at 800×g for 5 minutes, remove 900 μL ofsupernatant, and resuspend the pellet in remaining buffer.

Permeabilization

Disrupt the pellet by gentle tapping and add 1000 μL of ice cold BDPhosflow Perm Buffer III and incubate further on ice for 30 minutes.Centrifuge at 800×g for 5 minutes. Wash two more times with 1000 μL ofBD Stain buffer, remove supernatant except 100 uL of buffer after thelast wash.

Antibody Treatment

Disrupt the pellet by gentle tapping, add 100 uL of stain buffer and 5μL of pSTAT5_Alex488 (pY701) in all appropriate wells and mix properlyusing 200 μL multichannel pipet. Incubate plate overnight at 40° C. Add900 μL of BD stain buffer and centrifuge at 800×g for 5 minutes. Washone additional time with 1000 μL of buffer. Finally resuspend the pelletin 300 uL of BD stain buffer. Transfer the cells to 96-well v-bottomplate and acquire the cells in Beckman Coulter Cytoflex. Acquiring cellsin Flow Cytometer: Keep the threshold value to 250. Acquire at least8,000-10,000 cells.

APPENDIX Preparation of Reagents

RPMI 1640 Complete Medium: RPMI 1640 media+10% FBS.

Cytokine dilution: 1) IL-2 Stock at 100 ug/mL. Prepare a 0.5 ug/mLdilution by adding 5 uL of stock into 995 uL of cRPMI. Keep it on iceuntil used.

Lyse/Fix buffer preparation: Dilute 5× Lyse/Fix buffer to 1× using MQwater and keep at 37° C. until used.

BD Phosflow perm buffer III: Keep on ice/fridge

Compound Dilution

Final concentration, 10X Sample nM concentration Dilution 1 10,000100,000 2 μL of 10 mM compound + 198 μL of cRPMI media 2 3333.3 33,33360 μL of A + 120 μL of cRPMI media 3 1111.1 11,111 60 μL of B + 120 μLof cRPMI media 4 370.4 3,704 60 μL of C + 120 μL of cRPMI media 5 123.51,235 60 μL of D + 120 μL of cRPMI media 6 41.2 412 60 μL of E + 120 μLof cRPMI media 7 13.7 137 60 μL of F + 120 μL of cRPMI media 8 4.6 46 60μL of G + 120 μL of cRPMI media 9 0 0 2 μL of DMSO + 198 μL of cRPMImedia

Example 4: Co-Stimulation Assay in Lysed Whole Blood; JAK2: GM-CSFStimulated STAT5 Phosphorylation and JAK1/TYK2 Stimulated STAT1Phosphorylation Assay Human Blood Lysis Using Abcam's RBC Lysis Buffer

Dilute RBC lysis buffer to 1× in distilled water. Add 2 mL blood to 38mL of 1×RBC-lysis buffer. Incubate for 15 mins at RT, in dark. Spin at300 g, 5 mins, to collect the pellet. Re-lyse if necessary. Re-suspendpellet in 5 mL of cRPMI.

Compound and Cytokine Treatment

Aliquot 80 μL of lysed human blood in to wells of 96 deep-well plate.Add 10 μl of (10× conc.) of different concentrations of compounds to allwells except controls (unstained and unstimulated) and mix it with thehelp of 100 uL multichannel. Add 10 uL of RPMI media in controls. Fordilution of compounds and dilution range please refer Appendix. Incubateon water bath or CO₂ incubator for 1 hour at 37° C. Add 10 μl of (10×conc.) of cytokine mix (GM-CSF and IFNa) (final conc. 10 ng/mL of GM-CSFand 100 ng/mL of IFNa) to each well except unstimulated and unstainedcontrols and incubate further for 20 minutes on water bath at 37° C.

RBC Lysis and Fixation

Add 900 μL of prewarmed 1× Fix/Lyse solution (Appendix) and mix itproperly using 1000 μl multichannel, incubate further on water bath at37° C. for 10 minutes (which includes time of addition). Centrifuge at800× g for 5 minutes at 40° C.; remove 900 uL of supernatant and add 900μL of 1×PBS. Centrifuge at 800× g for 5 minutes at 40° C., remove 900 μLof supernatant. Wash one more time with 900 μL of PBS (optional) andresuspend pellets in 100 uL of PBS.

Permeabilization

Disrupt the pellet by gentle tapping and resuspend in 1000 μL of BDPhosflow Perm Buffer III and incubate plate on ice for 30 minutes.Centrifuge plate at 800× g for 5 minutes at 40° C. Wash two more timeswith 1000 μL of BD Pharmingen Stain Buffer.

Antibody Treatment

Disrupt the pellet by gentle tapping. Resuspend pellets in 100 uL ofStain Buffer and add 5 μL of pSTAT5_AF488 Ab and 5 uL of pSTAT1_PE inall wells except unstained control and mix properly using 200 μlmultichannel, incubate overnight at 40° C. Add 900 μL of wash buffer andcentrifuge at 1800 rpm for 3 minutes at 40° C. Wash one more time with1000 μL of BD Pharmingen Stain Buffer. Finally resuspend the pellet in300 uL of BD Pharmingen Stain Buffer. Transfer the cells to 96-wellv-bottom plate and acquire the cells in Beckman Coulter CytExpert.Acquiring cells in Flow Cytometer: Keep the threshold value to 250 andcell concentration should not exceed 100-500 cells/μL. Acquire at least5,000-10,000 cells.

APPENDIX Preparation of Reagents

RPMI 1640 Complete Medium: RPMI 1640 media+10% FBS.

Cytokine dilution: 1) GM-CSF Stock at 100 ug/mL. Prepare an intermediatedilution of 1 ug/mL by adding 2 uL of stock into 198 uL of cRPMI.Further dilute to 100 ng/mL by adding 100 uL of the intermediate stockto 900 uL of cRPMI. 2) IFNa Stock at 200 ug/mL. Dilute IFNa stock 1:200by adding 5 uL of stock into the 1000 uL of 100 ng/mL GM-CSF workingstock as above to give a combined working stock of 1000 ng/mL of IFNaand 100 ng/mL GM-CSF (10×). Keep it on ice until used.

Lyse/Fix buffer preparation: Dilute 5× Lyse/Fix buffer to 1× using MQwater and keep at 37° C. until used.

BD Phosflow perm buffer III: Keep on ice/fridge

Compound Dilution

Final 10X concentration, concentration, Sample nM nM Dilution 1 10,000100,000 2 μL of 10 mM compound + 198 μL of cRPMI media 2 3333.3 33,33360 μL of A + 120 μL of cRPMI media 3 1111.1 11,111 60 μL of B + 120 μLof cRPMI media 4 370.4 3,704 60 μL of C + 120 μL of cRPMI media 5 123.51,235 60 μL of D + 120 μL of cRPMI media 6 41.2 412 60 μL of E + 120 μLof cRPMI media 7 13.7 137 60 μL of F + 120 μL of cRPMI media 8 4.6 46 60μL of G + 120 μL of cRPMI media 9 0 0 2 μL of DMSO + 198 μL of cRPMImedia

The examples and embodiments described herein are for illustrativepurposes only and in some embodiments, various modifications or changesare to be included within the purview of disclosure and scope of theappended claims.

1. A compound of Formula (I′):

wherein:

is phenyl or a C₂-C₉heteroaryl ring;

is a C₂-C₉heterocycloalkyl ring; X is C(R₁₁) or N; L₁ is C₁-C₆alkyl orC₁-C₆heteroalkyl; L₂ is a bond or C₁-C₆alkyl; R₁ is C₃-C₉alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, or C₂-C₉heteroaryl, whereinC₃-C₉alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, orC₂-C₉heteroaryl are optionally substituted with 1, 2, or 3 R₅; each R₃is independently selected from halogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆heteroalkyl, —OR₇, —N(R₇)₂, —CN, —C(═O)R₈, —C(═O)OR₇, —C(═O)N(R₇)₂,—NR₇C(═O)R₈, —NR₇S(═O)₂R₈, —S(═O)₂R₈, and —S(═O)₂N(R₇)₂; R₄ is hydrogen,C₁-C₆alkyl, or C₁-C₆heteroalkyl; each R₅ is independently selected fromhalogen, oxo, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆heteroalkyl, —OR₇,—N(R₇)₂, —CN, —C(═O)R₈, —C(═O)OR₇, —C(═O)N(R₇)₂, —NR₇C(═O)R₈,—NR₇S(═O)₂R₈, —S(═O)₂R₈, and —S(═O)₂N(R₇)₂; each R₇ is independentlyselected from hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, andC₁-C₆heteroalkyl; each R₈ is independently selected from C₁-C₆alkyl,C₂-C₆alkenyl, C₁-C₆heteroalkyl, C₃-C₆cycloalkyl, andC₂-C₉heterocycloalkyl; R₁₁ is hydrogen or C₁-C₆alkyl optionallysubstituted with 1, 2, or 3 R₈; R₁₂ is hydrogen, halogen, or C₁-C₆alkyl;R₁₃ is selected from hydrogen and C₁-C₆alkyl; each R₁₄ is independentlyselected from C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆heteroalkyl, —OR₇,—N(R₇)₂, and oxo; n is 0, 1, 2, or 3; and p is 0, 1, 2, or 3; or apharmaceutically acceptable salt or solvate thereof.
 2. The compound ofclaim 1, or a pharmaceutically acceptable salt or solvate thereof,wherein

is a C₂-C₉heteroaryl ring.
 3. (canceled)
 4. The compound of claim 2, ora pharmaceutically acceptable salt or solvate thereof, wherein

is selected from pyrazolyl, pyrrolyl, and imidazolyl.
 5. The compound ofclaim 4, or a pharmaceutically acceptable salt or solvate thereof,having the structure of Formula (Ia′):


6. The compound of claim 5, or a pharmaceutically acceptable salt orsolvate thereof, wherein

is a pyrrolidine ring.
 7. The compound of claim 6, or a pharmaceuticallyacceptable salt or solvate thereof, wherein each R₁₄ is independentlyselected from C₁-C₆alkyl, C₁-C₆haloalkyl, and oxo.
 8. The compound ofclaim 7, or a pharmaceutically acceptable salt or solvate thereof,wherein each R₁₄ is independently selected from C₁-C₆alkyl.
 9. Thecompound of claim 8, or a pharmaceutically acceptable salt or solvatethereof, wherein p is
 1. 10.-17. (canceled)
 18. The compound of claim 6,or a pharmaceutically acceptable salt or solvate thereof, wherein L₂ isC₁-C₆alkyl.
 19. (canceled)
 20. The compound of claim 18, or apharmaceutically acceptable salt or solvate thereof, wherein L₁ isC₁-C₆alkyl.
 21. (canceled)
 22. (canceled)
 23. The compound of claim 20,or a pharmaceutically acceptable salt or solvate thereof, wherein R₁ isunsubstituted C₃-C₉alkyl.
 24. (canceled)
 25. (canceled)
 26. The compoundof claim 23, or a pharmaceutically acceptable salt or solvate thereof,wherein R₄ is hydrogen.
 27. (canceled)
 28. The compound of claim 26, ora pharmaceutically acceptable salt or solvate thereof, wherein R₁₂ ishydrogen.
 29. (canceled)
 30. (canceled)
 31. The compound claim 28, or apharmaceutically acceptable salt or solvate thereof, wherein n is 0.32.-36. (canceled)
 37. The compound of claim 31, or a pharmaceuticallyacceptable salt or solvate thereof, wherein X is C(H). 38.-47.(canceled)
 48. The compound of claim 37, or a pharmaceuticallyacceptable salt or solvate thereof, wherein R₁₃ is C₁-C₆alkyl. 49.(canceled)
 50. A compound selected from:

or a pharmaceutically acceptable salt or solvate thereof.
 51. (canceled)52. A pharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable excipient.
 53. A method of treating aninflammatory or autoimmune disease in a patient in need thereof,comprising administering to the patient a therapeutically effectiveamount of a compound of claim 1, or a pharmaceutically acceptable saltor solvate thereof.
 54. The method of claim 53, wherein the disease isselected from rheumatoid arthritis, multiple sclerosis, psoriasis,lupus, intestinal bowel disease, Crohn's disease, ulcerative colitis,ankylosing spondylitis, vitiligo, and atopic dermatitis.